International Journal of Molecular Sciences

25 pages, 12403 KiB

Open AccessReview

Unzippers, Resolvers and Sensors: A Structural and Functional Biochemistry Tale of RNA Helicases

by Ana Lúcia Leitão¹, Marina C. Costa² and Francisco J. Enguita^2,*

¹ Departamento de Ciências e Tecnologia da Biomassa, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Quinta da Torre, Campus de Caparica, 2829-516 Caparica, Portugal

² Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal

Int. J. Mol. Sci. 2015, 16(2), 2269-2293; https://doi.org/10.3390/ijms16022269 - 22 Jan 2015

Cited by 19 | Viewed by 13501

Abstract

The centrality of RNA within the biological world is an irrefutable fact that currently attracts increasing attention from the scientific community. The panoply of functional RNAs requires the existence of specific biological caretakers, RNA helicases, devoted to maintain the proper folding of those [...] Read more.

The centrality of RNA within the biological world is an irrefutable fact that currently attracts increasing attention from the scientific community. The panoply of functional RNAs requires the existence of specific biological caretakers, RNA helicases, devoted to maintain the proper folding of those molecules, resolving unstable structures. However, evolution has taken advantage of the specific position and characteristics of RNA helicases to develop new functions for these proteins, which are at the interface of the basic processes for transference of information from DNA to proteins. RNA helicases are involved in many biologically relevant processes, not only as RNA chaperones, but also as signal transducers, scaffolds of molecular complexes, and regulatory elements. Structural biology studies during the last decade, founded in X-ray crystallography, have characterized in detail several RNA-helicases. This comprehensive review summarizes the structural knowledge accumulated in the last two decades within this family of proteins, with special emphasis on the structure-function relationships of the most widely-studied families of RNA helicases: the DEAD-box, RIG-I-like and viral NS3 classes. Full article

(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)

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13 pages, 2427 KiB

Open AccessArticle

FBXW7 Acts as an Independent Prognostic Marker and Inhibits Tumor Growth in Human Osteosarcoma

by Zhanchun Li¹, Jie Xiao², Kongzu Hu³, Gang Wang⁴, Maoqiang Li⁵, Jidong Zhang^1,* and Guangqi Cheng¹

¹ Department of Orthopaedic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China

² Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China

³ Department of Orthopaedic Surgery, the First Affiliated Hospital of Anhui Medical University, Anhui 230022, China

⁴ Department of Orthopaedic Surgery, the Second Affiliated Hospital of Nanjing Medical University, Jiangsu 210029, China

⁵ Department of Orthopaedic Surgery, Hangzhou First People's Hospital, Zhejiang 310006, China

Int. J. Mol. Sci. 2015, 16(2), 2294-2306; https://doi.org/10.3390/ijms16022294 - 22 Jan 2015

Cited by 23 | Viewed by 7026

Abstract

F-box and WD repeat domain-containing 7 (FBXW7) is a potent tumor suppressor in human cancers including breast cancer, colorectal cancer, gastric cancer and hepatocellular carcinoma. In this study, we found that the expressions of FBXW7 protein and mRNA levels in osteosarcoma (OS) cases [...] Read more.

F-box and WD repeat domain-containing 7 (FBXW7) is a potent tumor suppressor in human cancers including breast cancer, colorectal cancer, gastric cancer and hepatocellular carcinoma. In this study, we found that the expressions of FBXW7 protein and mRNA levels in osteosarcoma (OS) cases were significantly lower than those in normal bone tissues. Clinical analysis indicated that FBXW7 was expressed at lower levels in OS patients with advanced clinical stage, high T classification and poor histological differentiation. Furthermore, we demonstrated that high expression of FBXW7 was correlated with a better 5-year survival of OS patients. Multivariate Cox regression analysis indicated that FBXW7 was an independent prognostic marker in OS. Our in vitro studies showed that FBXW7 overexpression inhibited cell cycle transition and cell proliferation, and promoted apoptosis in both U2OS and MG-63 cells. In a nude mouse xenograft model, FBXW7 overexpression slowed down tumor growth by inducing apoptosis and growth arrest. Mechanistically, FBXW7 inversely regulated oncoprotein c-Myc and cyclin E levels in both U2OS and MG-63 cells. Together these findings suggest that FBXW7 may serve as a prognostic biomarker and inhibit tumor progression by inducing apoptosis and growth arrest in OS. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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13 pages, 826 KiB

Open AccessArticle

Gentamicin Arrests Cancer Cell Growth: The Intriguing Involvement of Nuclear Sphingomyelin Metabolism

by Michela Codini^1,†, Samuela Cataldi^1,†

, Francesco Saverio Ambesi-Impiombato², Andrea Lazzarini³, Alessandro Floridi³, Remo Lazzarini³, Francesco Curcio², Tommaso Beccari¹ and Elisabetta Albi^3,*

¹ Department of Pharmaceutical Science, University of Perugia, Perugia 06122, Italy

² Department of Clinical and Biological Sciences, University of Udine, Udine 33100, Italy

³ Laboratory of Nuclear Lipid BioPathology, CRABiON, Perugia 06122, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 2307-2319; https://doi.org/10.3390/ijms16022307 - 22 Jan 2015

Cited by 23 | Viewed by 5869

Abstract

The use of gentamicin for the treatment of bacterial infection has always been an interesting and highly speculated issue for the scientific community. Conversely, its effect on cancer cells has been very little investigated. We studied the effect of high doses of gentamicin [...] Read more.

The use of gentamicin for the treatment of bacterial infection has always been an interesting and highly speculated issue for the scientific community. Conversely, its effect on cancer cells has been very little investigated. We studied the effect of high doses of gentamicin on non-Hodgkin’s T-cell human lymphoblastic lymphoma (SUP-T1). We showed that gentamicin delayed cell growth and induced cell death in lymphoma cells with a rather mild effect on lymphocytes. In SUP-T1 cells, GAPDH, B2M, CDKN1A and CDKN1B were down-expressed in comparison with lymphocytes. Gentamicin treatment in SUP-T1 cells restored the expression of GAPDH, B2M and CDKN1A to values similar to those of lymphocytes and caused overexpression of CDKN1B. The drug acted via sphingomyelin metabolism; in whole cells, sphingomyelinase activity was stimulated, whereas in purified nuclei, sphingomyelinase activity was inhibited and that of sphingomyelin-synthase was stimulated, with a consequent high level of nuclear sphingomyelin content. We suggest that the increase of nuclear sphingomyelin might enrich the nucleus of lipid microdomains that act as a platform for active chromatin and, thus, might be responsible for gene expression. It is possible that in lymphoblastic lymphoma, high doses of gentamicin induce a beneficial therapeutic outcome. Full article

(This article belongs to the Section Biochemistry)

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32 pages, 2015 KiB

Open AccessReview

Cyclic Nucleotide Signalling in Kidney Fibrosis

by Elisabeth Schinner, Veronika Wetzl and Jens Schlossmann^*

Pharmacology and Toxicology, University Regensburg, Regensburg 93053, Germany

Int. J. Mol. Sci. 2015, 16(2), 2320-2351; https://doi.org/10.3390/ijms16022320 - 22 Jan 2015

Cited by 48 | Viewed by 13100

Abstract

Kidney fibrosis is an important factor for the progression of kidney diseases, e.g., diabetes mellitus induced kidney failure, glomerulosclerosis and nephritis resulting in chronic kidney disease or end-stage renal disease. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were implicated to suppress [...] Read more.

Kidney fibrosis is an important factor for the progression of kidney diseases, e.g., diabetes mellitus induced kidney failure, glomerulosclerosis and nephritis resulting in chronic kidney disease or end-stage renal disease. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were implicated to suppress several of the above mentioned renal diseases. In this review article, identified effects and mechanisms of cGMP and cAMP regarding renal fibrosis are summarized. These mechanisms include several signalling pathways of nitric oxide/ANP/guanylyl cyclases/cGMP-dependent protein kinase and cAMP/Epac/adenylyl cyclases/cAMP-dependent protein kinase. Furthermore, diverse possible drugs activating these pathways are discussed. From these diverse mechanisms it is expected that new pharmacological treatments will evolve for the therapy or even prevention of kidney failure. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells 2014)

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14 pages, 2728 KiB

Open AccessArticle

Antiproliferative and Antioxidant Properties of Anthocyanin Rich Extracts from Blueberry and Blackcurrant Juice

by Zoriţa Diaconeasa¹, Loredana Leopold^1,*, Dumitriţa Rugină², Huseyin Ayvaz³ and Carmen Socaciu¹

¹ Faculty of Food Science and Technology, University of Agricultural Science and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, Cluj-Napoca 400372, Romania

² Faculty of Veterinary Medicine, University of Agricultural Science and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, Cluj-Napoca 400372, Romania

³ Department of Food Engineering, Canakkale Onsekiz Mart University, Canakkale 17020, Turkey

Int. J. Mol. Sci. 2015, 16(2), 2352-2365; https://doi.org/10.3390/ijms16022352 - 22 Jan 2015

Cited by 178 | Viewed by 16709

Abstract

The present study was aimed at evaluating the antiproliferative potential of anthocyanin-rich fractions (ARFs) obtained from two commercially available juices (blueberry and blackcurrant juices) on three tumor cell lines; B16F10 (murine melanoma), A2780 (ovarian cancer) and HeLa (cervical cancer). Individual anthocyanin determination, identification [...] Read more.

The present study was aimed at evaluating the antiproliferative potential of anthocyanin-rich fractions (ARFs) obtained from two commercially available juices (blueberry and blackcurrant juices) on three tumor cell lines; B16F10 (murine melanoma), A2780 (ovarian cancer) and HeLa (cervical cancer). Individual anthocyanin determination, identification and quantification were done using HPLC-MS. Antioxidant activity of the juices was determined through different mechanism methods such as DPPH and ORAC. For biological testing, the juices were purified through C₁₈ cartridges in order to obtain fractions rich in anthocyanins. The major anthocyanins identified were glycosylated cyanidin derivatives. The antiproliferative activity of the fractions was tested using the MTT assay. The antiproliferative potential of ARF was found to be associated with those bioactive molecules, anthocyanins due to their antioxidant potential. The results obtained indicated that both blueberry and blackcurrants are rich sources of antioxidants including anthocyanins and therefore these fruits are highly recommended for daily consumption to prevent numerous degenerative diseases. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables)

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20 pages, 1223 KiB

Open AccessReview

Oxidative Stress, Bone Marrow Failure, and Genome Instability in Hematopoietic Stem Cells

by Christine Richardson^*, Shan Yan and C. Greer Vestal

Department of Biological Sciences, UNC Charlotte, 9201 University City Blvd., Woodward Hall Room 386B, Charlotte, NC 28223, USA

Int. J. Mol. Sci. 2015, 16(2), 2366-2385; https://doi.org/10.3390/ijms16022366 - 22 Jan 2015

Cited by 60 | Viewed by 9768

Abstract

Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases [...] Read more.

Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)

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17 pages, 1276 KiB

Open AccessArticle

Quantitative Expression Analysis of APP Pathway and Tau Phosphorylation-Related Genes in the ICV STZ-Induced Non-Human Primate Model of Sporadic Alzheimer’s Disease

by Sang-Je Park^1,†, Young-Hyun Kim^1,†, Gyu-Hwi Nam¹, Se-Hee Choe^1,2, Sang-Rae Lee¹, Sun-Uk Kim¹, Ji-Su Kim¹, Bo-Woong Sim¹, Bong-Seok Song¹, Kang-Jin Jeong¹, Youngjeon Lee¹, Young Il Park³, Kyoung-Min Lee⁴, Jae-Won Huh^1,2,*

and Kyu-Tae Chang^1,2,*

¹ National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Korea

² University of Science & Technology, National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Korea

³ Graduate School Department of Digital Media, Ewha Womans University, Seoul 120-750, Korea

⁴ Department of Neurology, Seoul National University Hospital, Seoul 110-744, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 2386-2402; https://doi.org/10.3390/ijms16022386 - 22 Jan 2015

Cited by 23 | Viewed by 7232

Abstract

The accumulation and aggregation of misfolded proteins in the brain, such as amyloid-β (Aβ) and hyperphosphorylated tau, is a neuropathological hallmark of Alzheimer’s disease (AD). Previously, we developed and validated a novel non-human primate model for sporadic AD (sAD) research using intracerebroventricular administration [...] Read more.

The accumulation and aggregation of misfolded proteins in the brain, such as amyloid-β (Aβ) and hyperphosphorylated tau, is a neuropathological hallmark of Alzheimer’s disease (AD). Previously, we developed and validated a novel non-human primate model for sporadic AD (sAD) research using intracerebroventricular administration of streptozotocin (icv STZ). To date, no characterization of AD-related genes in different brain regions has been performed. Therefore, in the current study, the expression of seven amyloid precursor protein (APP) pathway-related and five tau phosphorylation-related genes was investigated by quantitative real-time PCR experiments, using two matched-pair brain samples from control and icv STZ-treated cynomolgus monkeys. The genes showed similar expression patterns within the control and icv STZ-treated groups; however, marked differences in gene expression patterns were observed between the control and icv STZ-treated groups. Remarkably, other than β-secretase (BACE1) and cyclin-dependent kinase 5 (CDK5), all the genes tested showed similar expression patterns in AD models compared to controls, with increased levels in the precuneus and occipital cortex. However, significant changes in gene expression patterns were not detected in the frontal cortex, hippocampus, or posterior cingulate. Based on these results, we conclude that APP may be cleaved via the general metabolic mechanisms of increased α- and γ-secretase levels, and that hyperphosphorylation of tau could be mediated by elevated levels of tau protein kinase, specifically in the precuneus and occipital cortex. Full article

(This article belongs to the Section Biochemistry)

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23 pages, 4678 KiB

Open AccessArticle

The Association between Polymorphism of INSR and Polycystic Ovary Syndrome: A Meta-Analysis

by Chun Feng^1,†, Ping-Ping Lv^1,†, Tian-Tian Yu¹, Min Jin², Jin-Ming Shen³, Xue Wang⁴, Feng Zhou¹ and Shi-Wen Jiang^4,*

¹ Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China

² Department of Reproductive Endocrinology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China

³ Department of Orthopedics, the First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou 310018, China

⁴ Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA 31404, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 2403-2425; https://doi.org/10.3390/ijms16022403 - 22 Jan 2015

Cited by 28 | Viewed by 8850

Abstract

Polycystic ovary syndrome (PCOS) is the most common gynecological endocrine disorder. The genetic background is believed to play a crucial role in the pathogenesis of PCOS. In recent years, the role of insulin receptor (INSR) polymorphisms in PCOS predisposition has attracted [...] Read more.

Polycystic ovary syndrome (PCOS) is the most common gynecological endocrine disorder. The genetic background is believed to play a crucial role in the pathogenesis of PCOS. In recent years, the role of insulin receptor (INSR) polymorphisms in PCOS predisposition has attracted much attention. We performed a meta-analysis to investigate the association between the single nucleotide polymorphisms (SNPs) of INSR and PCOS. Published literature from Pubmed, Embase, and Cochrane CENTRAL was retrieved up until 7 August 2014. A total of 20 case-control studies including 23,845 controls and 17,460 PCOS cases with an average Newcastle-Ottawa quality assessment scale (NOS) score of 6.75 were analyzed. Ninety-eight SNPs distributed in 23 exons and the flanking regions of INSR were investigated, among which 17 SNPs were found to be associated with PCOS. Three SNPs detected in more than three studies were selected for further analyses. Twelve studies including 1158 controls and 1264 PCOS cases entered the analysis of rs1799817, but no significant association was found for every genotype (p > 0.05). Further subgroup stratification by ethnicity and weight did not lead to discovery of significant correlation (p > 0.05). For rs2059806, four studies including 442 controls and 524 PCOS cases were qualified for meta-analysis, and no significant association with PCOS was found for any genotype (p > 0.05). Four studies including 12,830 controls and 11,683 PCOS cases investigated the correlation between rs2059807 and PCOS, and five of the six cohorts indicated a significant impact. Our current meta-analysis suggests no significant correlation between rs1799817/rs2059806 SNPs and susceptibility of PCOS, while rs2059807 could be a promising candidate SNP that might be involved in the susceptibility of PCOS. Full article

(This article belongs to the Special Issue Advances in Reproductive Biology)

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20 pages, 4916 KiB

Open AccessArticle

Trianthema portulacastrum Linn. Displays Anti-Inflammatory Responses during Chemically Induced Rat Mammary Tumorigenesis through Simultaneous and Differential Regulation of NF-κB and Nrf2 Signaling Pathways

by Animesh Mandal¹ and Anupam Bishayee^2,*

¹ Cancer Therapeutics and Chemoprevention Group, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA

² Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA 95757, USA

Int. J. Mol. Sci. 2015, 16(2), 2426-2445; https://doi.org/10.3390/ijms16022426 - 22 Jan 2015

Cited by 34 | Viewed by 7557

Abstract

Trianthema portulacastrum, a medicinal and dietary plant, has gained substantial importance due to its various pharmacological properties, including anti-inflammatory and anticarcinogenic activities. We have recently reported that a characterized T. portulacastrum extract (TPE) affords a considerable chemoprevention of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumorigenesis [...] Read more.

Trianthema portulacastrum, a medicinal and dietary plant, has gained substantial importance due to its various pharmacological properties, including anti-inflammatory and anticarcinogenic activities. We have recently reported that a characterized T. portulacastrum extract (TPE) affords a considerable chemoprevention of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumorigenesis though the underlying mechanisms are not completely understood. The objective of this study was to investigate anti-inflammatory mechanisms of TPE during DMBA mammary carcinogenesis in rats by monitoring cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-kappaB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). Mammary tumors were harvested from our previous study in which TPE (50–200 mg/kg) was found to inhibit mammary tumorigenesis in a dose-response manner. The expressions of intratumor COX-2, HSP90, NF-κB, inhibitory kappaB-alpha (IκBα) and Nrf2 were determined by immunohistochemistry. TPE downregulated the expression of COX-2 and HSP90, blocked the degradation of IκBα, hampered the translocation of NF-κB from cytosol to nucleus and upregulated the expression and nuclear translocation of Nrf2 during DMBA mammary carcinogenesis. These results in conjunction with our previous findings suggest that TPE prevents DMBA-induced breast neoplasia by anti-inflammatory mechanisms mediated through simultaneous and differential modulation of two interconnected molecular circuits, namely NF-κB and Nrf2 signaling pathways. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals in Functional Foods for Cancer Prevention)

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12 pages, 2279 KiB

Open AccessArticle

Ameliorative Effects of 5-Hydroxymethyl-2-furfural (5-HMF) from Schisandra chinensis on Alcoholic Liver Oxidative Injury in Mice

by Wei Li^1,2, Xin-Nan Qu², Ye Han², Si-Wen Zheng¹, Jia Wang^1,2 and Ying-Ping Wang^1,*

¹ Institute of Special Wild Economic Animals and Plant, Chinese Academy of Agricultural Sciences, Changchun 132109, China

² College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China

Int. J. Mol. Sci. 2015, 16(2), 2446-2457; https://doi.org/10.3390/ijms16022446 - 22 Jan 2015

Cited by 90 | Viewed by 10380

Abstract

The aim of this paper is to evaluate the protective effect of 5-hydroxymethyl-2-furfural (5-HMF) on acute alcohol-induced liver oxidative injury in mice. 5-HMF, a maillard reaction product, was isolated from the fruits of Schisandra chinensis for animal experiments. Experimental ICR mice were pretreated [...] Read more.

The aim of this paper is to evaluate the protective effect of 5-hydroxymethyl-2-furfural (5-HMF) on acute alcohol-induced liver oxidative injury in mice. 5-HMF, a maillard reaction product, was isolated from the fruits of Schisandra chinensis for animal experiments. Experimental ICR mice were pretreated with different doses of 5-HMF (7.5, 15, and 30 mg/kg) for seven days by gavage feeding. Biochemical markers and enzymatic antioxidants from serum and liver tissue were examined. Our results showed that the activities of ALT (alanine aminotransferase), AST (aspartate transaminase), TC (total cholesterol), TG (triglyceride), L-DLC (low density lipoprotein) in serum and the levels of MDA (malondialdehyde) in liver tissue, decreased significantly (p < 0.05) in the 5-HMF-treated group compared with the alcohol group. On the contrary, enzymatic antioxidants CAT (catalase), GSH-Px (glutathione peroxidase), and GSH SOD (superoxide dismutase) were markedly elevated in liver tissue treated with 5-HMF (p < 0.05). Furthermore, the hepatic levels of pro-inflammatory response marker tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) were significantly suppressed (p < 0.05). Histopathological examination revealed that 5-HMF (30 mg/kg) pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It is suggested that the hepatoprotective effects exhibited by 5-HMF on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 1470 KiB

Open AccessArticle

Expression of the SIRT2 Gene and Its Relationship with Body Size Traits in Qinchuan Cattle (Bos taurus)

by Lin-Sheng Gui^1,†, Ya-Ran Zhang^1,†, Gui-Yao Liu² and Lin-Sen Zan^1,3,*

¹ College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China

² Institute of Soil and Water Conservation, Chinese Academy of Science and Ministry of Water Resource, Yangling 712100, China

³ National Beef Cattle Improvement Center of Northwest A&F University, Yangling 712100, China

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2015, 16(2), 2458-2471; https://doi.org/10.3390/ijms16022458 - 22 Jan 2015

Cited by 20 | Viewed by 6237

Abstract

Silent information regulator 2 (SIRT2) is a member of the sirtuin family of class III NAD (nicotinamide adenine dinucleotide)-dependent protein deacetylases and may regulate senescence, metabolism and apoptosis. The aims of this study were to investigate whether the SIRT2 gene could be used [...] Read more.

Silent information regulator 2 (SIRT2) is a member of the sirtuin family of class III NAD (nicotinamide adenine dinucleotide)-dependent protein deacetylases and may regulate senescence, metabolism and apoptosis. The aims of this study were to investigate whether the SIRT2 gene could be used as a candidate gene in the breeding of Qinchuan cattle. Real-time polymerase chain reaction (RT-PCR) results showed that among all types of tissue that were analyzed, the highest mRNA expression levels of the gene were found in subcutaneous fat. DNA sequencing of 468 individual Qinchuan cattle identified two novel, single nucleotide polymorphisms (g.19501 C > T and g.19518 C > T) in the 3' untranslated region (3'UTR) of the SIRT2 gene. The frequencies of SNP g.19501 C > T and g.19518 C > T were in Hardy-Weinberg disequilibrium in all the samples (chi-square test, χ² < χ_0.05²). An association analysis showed that the two loci were significantly correlated with some body size traits and the H₂H₂ (-CT-CT-) diplotypes performed better than other combinations. These results indicated that the variations in the SIRT2 gene and their corresponding genotypes may be considered as molecular markers for economic traits in cattle breeding. Full article

(This article belongs to the Section Biochemistry)

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25 pages, 731 KiB

Open AccessReview

Promoter Hypermethylation of Tumour Suppressor Genes as Potential Biomarkers in Colorectal Cancer

by Jennifer Mun-Kar Ng and Jun Yu^*

Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China

Int. J. Mol. Sci. 2015, 16(2), 2472-2496; https://doi.org/10.3390/ijms16022472 - 22 Jan 2015

Cited by 155 | Viewed by 10800

Abstract

Colorectal cancer (CRC) is a common malignancy and the fourth leading cause of cancer deaths worldwide. It results from the accumulation of multiple genetic and epigenetic changes leading to the transformation of colon epithelial cells into invasive adenocarcinomas. In CRC, epigenetic changes, in [...] Read more.

Colorectal cancer (CRC) is a common malignancy and the fourth leading cause of cancer deaths worldwide. It results from the accumulation of multiple genetic and epigenetic changes leading to the transformation of colon epithelial cells into invasive adenocarcinomas. In CRC, epigenetic changes, in particular promoter CpG island methylation, occur more frequently than genetic mutations. Hypermethylation contributes to carcinogenesis by inducing transcriptional silencing or downregulation of tumour suppressor genes and currently, over 600 candidate hypermethylated genes have been identified. Over the past decade, a deeper understanding of epigenetics coupled with technological advances have hinted at the potential of translating benchtop research into biomarkers for clinical use. DNA methylation represents one of the largest bodies of literature in epigenetics, and hence has the highest potential for minimally invasive biomarker development. Most progress has been made in the development of diagnostic markers and there are currently two, one stool-based and one blood-based, biomarkers that are commercially available for diagnostics. Prognostic and predictive methylation markers are still at their infantile stages. Full article

(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)

20 pages, 2704 KiB

Open AccessArticle

Chemical Constituents Analysis and Antidiabetic Activity Validation of Four Fern Species from Taiwan

by Chen-Yu Chen^1,2, Fu-Yu Chiu³, Yenshou Lin³, Wei-Jan Huang^1,2, Po-Shiuan Hsieh^4,† and Feng-Lin Hsu^1,2,*,†

¹ College of Pharmacy, School of Pharmacy, Taipei Medical University, 250 Wuxing St., Taipei 110, Taiwan

² Graduate Institute of Pharmacognosy, School of Pharmacy, Taipei Medical University, 250 Wuxing St., Taipei 110, Taiwan

³ Department of Life Science, National Taiwan Normal University, No. 162, Sec. 1, Heping E. Rd., Taipei 106, Taiwan

⁴ Department of Physiology and Biophysics, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Rd., Taipei 114, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 2497-2516; https://doi.org/10.3390/ijms16022497 - 22 Jan 2015

Cited by 22 | Viewed by 7119

Abstract

Pterosins are abundant in ferns, and pterosin A was considered a novel activator of adenosine monophosphate-activated protein kinase, which is crucial for regulating blood glucose homeostasis. However, the distribution of pterosins in different species of ferns from various places in Taiwan is currently [...] Read more.

Pterosins are abundant in ferns, and pterosin A was considered a novel activator of adenosine monophosphate-activated protein kinase, which is crucial for regulating blood glucose homeostasis. However, the distribution of pterosins in different species of ferns from various places in Taiwan is currently unclear. To address this question, the distribution of pterosins, glucose-uptake efficiency, and protective effects of pterosin A on β-cells were examined. Our results showed that three novel compounds, 13-chloro-spelosin 3-O-β-d-glucopyranoside (1), (3R)-Pterosin D 3-O-β-d-(3'-p-coumaroyl)-glucopyranoside (2), and (2R,3R)-Pterosin L 3-O-β-d-(3'-p-coumaroyl)-glucopyranoside (3), were isolated for the first time from four fern species (Ceratopteris thalictroides, Hypolepis punctata, Nephrolepis multiflora, and Pteridium revolutum) along with 27 known compounds. We also examined the distribution of these pterosin compounds in the mentioned fern species (except N. multiflora). Although all pterosin analogs exhibited the same effects in glucose uptake assays, pterosin A prevented cell death and reduced reactive oxygen species (ROS) production. This paper is the first report to provide new insights into the distribution of pterosins in ferns from Taiwan. The potential anti-diabetic activity of these novel phytocompounds warrants further functional studies. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 1026 KiB

Open AccessArticle

The Influence of AHI1 Variants on the Diagnosis and Treatment Outcome in Schizophrenia

by Stefano Porcelli¹, Chi-Un Pae^2,3,*, Changsu Han⁴, Soo-Jung Lee², Ashwin A. Patkar³, Prakash S. Masand⁵, Beatrice Balzarro¹, Siegfried Alberti¹, Diana De Ronchi¹ and Alessandro Serretti¹

¹ Institute of Psychiatry, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna 40123, Italy

² Department of Psychiatry, the Catholic University of Korea College of Medicine, Seoul 137701, Korea

³ Department of Psychiatry and Behavioural Sciences, Duke University Medical Center, Durham, NC 27710, USA

⁴ Department of Psychiatry, Korea University, College of Medicine, Seoul 136701, Korea

⁵ Global Medical Education, New York, NY 15260, USA

Int. J. Mol. Sci. 2015, 16(2), 2517-2529; https://doi.org/10.3390/ijms16022517 - 22 Jan 2015

Cited by 11 | Viewed by 5737

Abstract

The present study aimed to explore whether four single nucleotide polymorphisms (SNPs) within the AHI1 gene could be associated with schizophrenia (SCZ) and whether they could predict the clinical outcomes in SCZ patients treated with antipsychotics. Four hundred twenty-six (426) in-patients with SCZ [...] Read more.

The present study aimed to explore whether four single nucleotide polymorphisms (SNPs) within the AHI1 gene could be associated with schizophrenia (SCZ) and whether they could predict the clinical outcomes in SCZ patients treated with antipsychotics. Four hundred twenty-six (426) in-patients with SCZ and 345 controls were genotyped for four AHI1 SNPs (rs11154801, rs7750586, rs9647635 and rs9321501). Baseline and clinical measures for SCZ patients were assessed through the Positive and Negative Syndrome Scale (PANSS). Allelic and genotypic frequencies in SCZ subjects were compared with those of controls using the χ² statistics. The repeated-measure ANOVA was used for the assessment of treatment outcomes measured by PANSS changes. The case-control analysis did not show any difference in the genotypic distribution of the SNPs, while in the allelic analysis, a weak association was found between the rs9647635 A allele and SCZ. Furthermore, in the haplotype analysis, three haplotypes resulted in being associated with SCZ. On the other hand, two SNPs (rs7750586 and rs9647635) were associated with clinical improvement of negative symptoms in the allelic analysis, although in the genotypic analysis, only trends of association were found for the same SNPs. Our findings suggest a possible influence of AHI1 variants on SCZ susceptibility and antipsychotic response, particularly concerning negative symptomatology. Subsequent well-designed studies would be mandatory to confirm our results due to the methodological shortcomings of the present study. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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29 pages, 4483 KiB

Open AccessArticle

EGCG Inhibits Proliferation, Invasiveness and Tumor Growth by Up-Regulation of Adhesion Molecules, Suppression of Gelatinases Activity, and Induction of Apoptosis in Nasopharyngeal Carcinoma Cells

by Chih-Yeu Fang^1,2,*, Chung-Chun Wu², Hui-Yu Hsu^2,3,4, Hsin-Ying Chuang², Sheng-Yen Huang^2,3,4, Ching-Hwa Tsai⁵, Yao Chang⁶, George Sai-Wah Tsao⁷, Chi-Long Chen^1,8 and Jen-Yang Chen^2,5,*

¹ Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan

² National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan

³ Graduate Program of Biotechnology in Medicine of National Tsing Hua University and National Health Research Institutes, Hsinchu 300, Taiwan

⁴ Institute of Biotechnology, Department of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan

⁵ Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan

⁶ National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 701, Taiwan

⁷ Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

⁸ Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan

Int. J. Mol. Sci. 2015, 16(2), 2530-2558; https://doi.org/10.3390/ijms16022530 - 23 Jan 2015

Cited by 62 | Viewed by 7855

Abstract

(−)-Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, has been shown to inhibit the proliferation of a variety of tumor cells. Epidemiological studies have shown that drinking green tea can reduce the incidence of nasopharyngeal carcinoma (NPC), yet the underlying mechanism is [...] Read more.

(−)-Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, has been shown to inhibit the proliferation of a variety of tumor cells. Epidemiological studies have shown that drinking green tea can reduce the incidence of nasopharyngeal carcinoma (NPC), yet the underlying mechanism is not well understood. In this study, the inhibitory effect of EGCG was tested on a set of Epstein Barr virus-negative and -positive NPC cell lines. Treatment with EGCG inhibited the proliferation of NPC cells but did not affect the growth of a non-malignant nasopharyngeal cell line, NP460hTert. Moreover, EGCG treated cells had reduced migration and invasive properties. The expression of the cell adhesion molecules E-cadherin and β-catenin was found to be up-regulated by EGCG treatment, while the down-regulation of matrix metalloproteinases (MMP)-2 and MMP-9 were found to be mediated by suppression of extracellular signal-regulated kinase (ERK) phosphorylation and AP-1 and Sp1 transactivation. Spheroid formation by NPC cells in suspension was significantly inhibited by EGCG. Oral administration of EGCG was capable of suppressing tumor growth in xenografted mice bearing NPC tumors. Treatment with EGCG was found to elevate the expression of p53 and p21, and eventually led to apoptosis of NPC cells via caspase 3 activation. The nuclear translocation of NF-κB and β-catenin was also suppressed by EGCG treatment. These results indicate that EGCG can inhibit the proliferation and invasiveness, and induce apoptosis, of NPC cells, making it a promising agent for chemoprevention or adjuvant therapy of NPC. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 1894 KiB

Open AccessArticle

Sinomenine Hydrochloride Protects against Polymicrobial Sepsis via Autophagy

by Yu Jiang¹, Min Gao², Wenmei Wang¹, Yuejiao Lang¹, Zhongyi Tong¹, Kangkai Wang¹, Huali Zhang¹, Guangwen Chen¹, Meidong Liu¹, Yongming Yao³ and Xianzhong Xiao^1,*

¹ Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China

² Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, Changsha 410013, China

³ Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100037, China

Int. J. Mol. Sci. 2015, 16(2), 2559-2573; https://doi.org/10.3390/ijms16022559 - 23 Jan 2015

Cited by 58 | Viewed by 8076

Abstract

Sepsis, a systemic inflammatory response to infection, is the major cause of death in intensive care units (ICUs). The mortality rate of sepsis remains high even though the treatment and understanding of sepsis both continue to improve. Sinomenine (SIN) is a natural alkaloid [...] Read more.

Sepsis, a systemic inflammatory response to infection, is the major cause of death in intensive care units (ICUs). The mortality rate of sepsis remains high even though the treatment and understanding of sepsis both continue to improve. Sinomenine (SIN) is a natural alkaloid extracted from Chinese medicinal plant Sinomenium acutum, and its hydrochloride salt (Sinomenine hydrochloride, SIN-HCl) is widely used to treat rheumatoid arthritis (RA). However, its role in sepsis remains unclear. In the present study, we investigated the role of SIN-HCl in sepsis induced by cecal ligation and puncture (CLP) in BALB/c mice and the corresponding mechanism. SIN-HCl treatment improved the survival of BALB/c mice that were subjected to CLP and reduced multiple organ dysfunction and the release of systemic inflammatory mediators. Autophagy activities were examined using Western blotting. The results showed that CLP-induced autophagy was elevated, and SIN-HCl treatment further strengthened the autophagy activity. Autophagy blocker 3-methyladenine (3-MA) was used to investigate the mechanism of SIN-HCl in vitro. Autophagy activities were determined by examining the autophagosome formation, which was shown as microtubule-associated protein light chain 3 (LC3) puncta with green immunofluorescence. SIN-HCl reduced lipopolysaccharide (LPS)-induced inflammatory cytokine release and increased autophagy in peritoneal macrophages (PM). 3-MA significantly decreased autophagosome formation induced by LPS and SIN-HCl. The decrease of inflammatory cytokines caused by SIN-HCl was partially aggravated by 3-MA treatment. Taken together, our results indicated that SIN-HCl could improve survival, reduce organ damage, and attenuate the release of inflammatory cytokines induced by CLP, at least in part through regulating autophagy activities. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 6835 KiB

Open AccessArticle

IgG and IgA with Potential Microbial-Binding Activity Are Expressed by Normal Human Skin Epidermal Cells

by Dongyang Jiang^1,2,3, Jing Ge^1,2, Qinyuan Liao^1,2, Junfan Ma^1,2, Yang Liu^1,2, Jing Huang^1,2, Chong Wang^1,2, Weiyan Xu^1,2, Jie Zheng⁴, Wenwei Shao^1,2, Gregory Lee⁵ and Xiaoyan Qiu^1,2,3,*

¹ Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China

² Center for Human Disease Genomics, Peking University, Beijing 100191, China

³ Key Laboratory of Medical Immunology, Ministry of Health, Beijing 100191, China

⁴ Hematology Oncology Center, Beijing Children's Hospital, Beijing 100045, China

⁵ Andrology Laboratory, University of British Columbia Center for Reproductive Health, Vancouver, BC V6H 3N1, Canada

Int. J. Mol. Sci. 2015, 16(2), 2574-2590; https://doi.org/10.3390/ijms16022574 - 23 Jan 2015

Cited by 37 | Viewed by 8798

Abstract

The innate immune system of the skin is thought to depend largely on a multi-layered mechanical barrier supplemented by epidermis-derived antimicrobial peptides. To date, there are no reports of antimicrobial antibody secretion by the epidermis. In this study, we report the expression of [...] Read more.

The innate immune system of the skin is thought to depend largely on a multi-layered mechanical barrier supplemented by epidermis-derived antimicrobial peptides. To date, there are no reports of antimicrobial antibody secretion by the epidermis. In this study, we report the expression of functional immunoglobulin G (IgG) and immunoglobulin A (IgA), previously thought to be only produced by B cells, in normal human epidermal cells and the human keratinocyte line HaCaT. While B cells express a fully diverse Ig, epidermal cell-expressed IgG or IgA showed one or two conservative V_HDJ_H rearrangements in each individual. These unique VDJ rearrangements in epidermal cells were found neither in the B cell-derived Ig VDJ databases published by others nor in our positive controls. IgG and IgA from epidermal cells of the same individual had different VDJ rearrangement patterns. IgG was found primarily in prickle cells, and IgA was mainly detected in basal cells. Both epidermal cell-derived IgG and IgA showed potential antibody activity by binding pathogens like Staphylococcus aureus, the most common pathogenic skin bacteria, but the microbial-binding profile was different. Our data indicates that normal human epidermal cells spontaneously express IgG and IgA, and we speculate that these Igs participate in skin innate immunity. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 1063 KiB

Open AccessReview

Rescue Effects: Irradiated Cells Helped by Unirradiated Bystander Cells

by R. K. K. Lam¹, Y. K. Fung¹, W. Han² and K. N. Yu^1,3,*

¹ Department of Physics and Materials Science, City University of Hong Kong, Kowloon, Hong Kong

² Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China

³ State Key Laboratory in Marine Pollution, City University of Hong Kong, Kowloon, Hong Kong

Int. J. Mol. Sci. 2015, 16(2), 2591-2609; https://doi.org/10.3390/ijms16022591 - 23 Jan 2015

Cited by 38 | Viewed by 8457

Abstract

The rescue effect describes the phenomenon where irradiated cells or organisms derive benefits from the feedback signals sent from the bystander unirradiated cells or organisms. An example of the benefit is the mitigation of radiation-induced DNA damages in the irradiated cells. The rescue [...] Read more.

The rescue effect describes the phenomenon where irradiated cells or organisms derive benefits from the feedback signals sent from the bystander unirradiated cells or organisms. An example of the benefit is the mitigation of radiation-induced DNA damages in the irradiated cells. The rescue effect can compromise the efficacy of radioimmunotherapy (RIT) (and actually all radiotherapy). In this paper, the discovery and subsequent confirmation studies on the rescue effect were reviewed. The mechanisms and the chemical messengers responsible for the rescue effect studied to date were summarized. The rescue effect between irradiated and bystander unirradiated zebrafish embryos in vivo sharing the same medium was also described. In the discussion section, the mechanism proposed for the rescue effect involving activation of the nuclear factor κB (NF-κB) pathway was scrutinized. This mechanism could explain the promotion of cellular survival and correct repair of DNA damage, dependence on cyclic adenosine monophosphate (cAMP) and modulation of intracellular reactive oxygen species (ROS) level in irradiated cells. Exploitation of the NF-κB pathway to improve the effectiveness of RIT was proposed. Finally, the possibility of using zebrafish embryos as the model to study the efficacy of RIT in treating solid tumors was also discussed. Full article

(This article belongs to the Special Issue Frontiers of Radioimmunotherapy)

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16 pages, 952 KiB

Open AccessReview

Insight into the Molecular and Functional Diversity of Cnidarian Neuropeptides

by Toshio Takahashi^1,* and Noriyo Takeda²

¹ Suntory Foundation for Life Sciences, Bioorganic Research Institute, Osaka 618-8503, Japan

² Research Center for Marine Biology, Asamushi, Graduate School of Life Sciences, Tohoku University, Aomori 039-3501, Japan

Int. J. Mol. Sci. 2015, 16(2), 2610-2625; https://doi.org/10.3390/ijms16022610 - 23 Jan 2015

Cited by 30 | Viewed by 8508

Abstract

Cnidarians are the most primitive animals to possess a nervous system. This phylum is composed of the classes Scyphozoa (jellyfish), Cubozoa (box jellyfish), and Hydrozoa (e.g., Hydra, Hydractinia), which make up the subphylum Medusozoa, as well as the class Anthozoa (sea [...] Read more.

Cnidarians are the most primitive animals to possess a nervous system. This phylum is composed of the classes Scyphozoa (jellyfish), Cubozoa (box jellyfish), and Hydrozoa (e.g., Hydra, Hydractinia), which make up the subphylum Medusozoa, as well as the class Anthozoa (sea anemones and corals). Neuropeptides have an early evolutionary origin and are already abundant in cnidarians. For example, from the cnidarian Hydra, a key model system for studying the peptides involved in developmental and physiological processes, we identified a wide variety of novel neuropeptides from Hydra magnipapillata (the Hydra Peptide Project). Most of these peptides act directly on muscle cells and induce contraction and relaxation. Some peptides are involved in cell differentiation and morphogenesis. In this review, we describe FMRFamide-like peptides (FLPs), GLWamide-family peptides, and the neuropeptide Hym-355; FPQSFLPRGamide. Several hundred FLPs have been isolated from invertebrate animals such as cnidarians. GLWamide-family peptides function as signaling molecules in muscle contraction, metamorphosis, and settlement in cnidarians. Hym-355; FPQSFLPRGamide enhances neuronal differentiation in Hydra. Recently, GLWamide-family peptides and Hym-355; FPQSFLPRGamide were shown to trigger oocyte maturation and subsequent spawning in the hydrozoan jellyfish Cytaeis uchidae. These findings suggest the importance of these neuropeptides in both developmental and physiological processes. Full article

(This article belongs to the Special Issue Bioactive Carbohydrates and Peptides)

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15 pages, 1989 KiB

Open AccessReview

Fatal Attraction: How Bacterial Adhesins Affect Host Signaling and What We Can Learn from Them

by Daniel H. Stones and Anne-Marie Krachler^*

Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK

Int. J. Mol. Sci. 2015, 16(2), 2626-2640; https://doi.org/10.3390/ijms16022626 - 23 Jan 2015

Cited by 45 | Viewed by 14151

Abstract

The ability of bacterial species to colonize and infect host organisms is critically dependent upon their capacity to adhere to cellular surfaces of the host. Adherence to cell surfaces is known to be essential for the activation and delivery of certain virulence factors, [...] Read more.

The ability of bacterial species to colonize and infect host organisms is critically dependent upon their capacity to adhere to cellular surfaces of the host. Adherence to cell surfaces is known to be essential for the activation and delivery of certain virulence factors, but can also directly affect host cell signaling to aid bacterial spread and survival. In this review we will discuss the recent advances in the field of bacterial adhesion, how we are beginning to unravel the effects adhesins have on host cell signaling, and how these changes aid the bacteria in terms of their survival and evasion of immune responses. Finally, we will highlight how the exploitation of bacterial adhesins may provide new therapeutic avenues for the treatment of a wide range of bacterial infections. Full article

(This article belongs to the Special Issue Bioactive Carbohydrates and Peptides)

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22 pages, 1469 KiB

Open AccessReview

Autophagy in DNA Damage Response

by Piotr Czarny¹, Elzbieta Pawlowska², Jolanta Bialkowska-Warzecha³, Kai Kaarniranta^4,5 and Janusz Blasiak^1,*

¹ Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland

² Department of Orthodontics, Medical University of Lodz, Pomorska 251, 92-216 Lodz, Poland

³ Department of Infectious and Liver Diseases, Medical University of Lodz, Kniaziewicza 1/5, 92-347 Lodz, Poland

⁴ Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio FI-70211, Finland

⁵ Department of Ophthalmology, Kuopio University Hospital, Kuopio FI-70211, Finland

Int. J. Mol. Sci. 2015, 16(2), 2641-2662; https://doi.org/10.3390/ijms16022641 - 23 Jan 2015

Cited by 132 | Viewed by 22018

Abstract

DNA damage response (DDR) involves DNA repair, cell cycle regulation and apoptosis, but autophagy is also suggested to play a role in DDR. Autophagy can be activated in response to DNA-damaging agents, but the exact mechanism underlying this activation is not fully understood, [...] Read more.

DNA damage response (DDR) involves DNA repair, cell cycle regulation and apoptosis, but autophagy is also suggested to play a role in DDR. Autophagy can be activated in response to DNA-damaging agents, but the exact mechanism underlying this activation is not fully understood, although it is suggested that it involves the inhibition of mammalian target of rapamycin complex 1 (mTORC1). mTORC1 represses autophagy via phosphorylation of the ULK1/2–Atg13–FIP200 complex thus preventing maturation of pre-autophagosomal structures. When DNA damage occurs, it is recognized by some proteins or their complexes, such as poly(ADP)ribose polymerase 1 (PARP-1), Mre11–Rad50–Nbs1 (MRN) complex or FOXO3, which activate repressors of mTORC1. SQSTM1/p62 is one of the proteins whose levels are regulated via autophagic degradation. Inhibition of autophagy by knockout of FIP200 results in upregulation of SQSTM1/p62, enhanced DNA damage and less efficient damage repair. Mitophagy, one form of autophagy involved in the selective degradation of mitochondria, may also play role in DDR. It degrades abnormal mitochondria and can either repress or activate apoptosis, but the exact mechanism remains unknown. There is a need to clarify the role of autophagy in DDR, as this process may possess several important biomedical applications, involving also cancer therapy. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)

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15 pages, 727 KiB

Open AccessArticle

Bone-Remodeling Transcript Levels Are Independent of Perching in End-of-Lay White Leghorn Chickens

by Maurice D. Dale¹, Erin M. Mortimer¹, Santharam Kolli¹, Erik Achramowicz¹, Glenn Borchert^1,2, Steven A. Juliano¹, Scott Halkyard¹, Nick Sietz¹, Craig Gatto¹

, Patricia Y. Hester³ and David A. Rubin^1,*

¹ School of Biological Sciences, Illinois State University, Normal, IL 61701, USA

² Department of Biology, University of South Alabama, Mobile, AL 36688, USA

³ Department of Animal Sciences, Purdue University, 125 South Russell St, West Lafayette, IN 47907, USA

Int. J. Mol. Sci. 2015, 16(2), 2663-2677; https://doi.org/10.3390/ijms16022663 - 23 Jan 2015

Cited by 12 | Viewed by 7099

Abstract

Osteoporosis is a bone disease that commonly results in a 30% incidence of fracture in hens used to produce eggs for human consumption. One of the causes of osteoporosis is the lack of mechanical strain placed on weight-bearing bones. In conventionally-caged hens, there [...] Read more.

Osteoporosis is a bone disease that commonly results in a 30% incidence of fracture in hens used to produce eggs for human consumption. One of the causes of osteoporosis is the lack of mechanical strain placed on weight-bearing bones. In conventionally-caged hens, there is inadequate space for chickens to exercise and induce mechanical strain on their bones. One approach is to encourage mechanical stress on bones by the addition of perches to conventional cages. Our study focuses on the molecular mechanism of bone remodeling in end-of-lay hens (71 weeks) with access to perches. We examined bone-specific transcripts that are actively involved during development and remodeling. Using real-time quantitative PCR, we examined seven transcripts (COL2A1 (collagen, type II, alpha 1), RANKL (receptor activator of nuclear factor kappa-B ligand), OPG (osteoprotegerin), PTHLH (PTH-like hormone), PTH1R (PTH/PTHLH type-1 receptor), PTH3R (PTH/PTHLH type-3 receptor), and SOX9 (Sry-related high mobility group box)) in phalange, tibia and femur. Our results indicate that the only significant effect was a difference among bones for COL2A1 (femur > phalange). Therefore, we conclude that access to a perch did not alter transcript expression. Furthermore, because hens have been used as a model for human bone metabolism and osteoporosis, the results indicate that bone remodeling due to mechanical loading in chickens may be a product of different pathways than those involved in the mammalian model. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 2227 KiB

Open AccessArticle

Novel Localization of Peripherin 2, the Photoreceptor-Specific Retinal Degeneration Slow Protein, in Retinal Pigment Epithelium

by Patrizia B. Uhl¹, Barbara Amann¹, Stefanie M. Hauck²

and Cornelia A. Deeg^1,*

¹ Institute for Animal Physiology, Department of Veterinary Sciences, Ludwig-Maximilians-University, Veterinärstraße 13, D-80539 Munich, Germany

² Research Unit for Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany

Int. J. Mol. Sci. 2015, 16(2), 2678-2692; https://doi.org/10.3390/ijms16022678 - 26 Jan 2015

Cited by 4 | Viewed by 6006

Abstract

Retinal pigment epithelium (RPE) builds the outer blood-retinal barrier of the eye. Since one typical feature of the autoimmune disease, equine recurrent uveitis (ERU), is the breakdown of this barrier, we recently performed comparative analysis of healthy and uveitic RPE. We identified for [...] Read more.

Retinal pigment epithelium (RPE) builds the outer blood-retinal barrier of the eye. Since one typical feature of the autoimmune disease, equine recurrent uveitis (ERU), is the breakdown of this barrier, we recently performed comparative analysis of healthy and uveitic RPE. We identified for the first time peripherin 2, which is responsible for visual perception and retina development, to be localized in RPE. The purpose of this study was therefore to validate our findings by characterizing the expression patterns of peripherin 2 in RPE and retina. We also investigated whether peripherin 2 expression changes in ERU and if it is expressed by the RPE itself. Via immunohistochemistry, significant downregulation of peripherin 2 in uveitic RPE compared to the control was detectable, but there was no difference in healthy and uveitic retina. A further interesting finding was the clear distinction between peripherin 2 and the phagocytosis marker, rhodopsin, in healthy RPE. In conclusion, changes in the expression pattern of peripherin 2 selectively affect RPE, but not retina, in ERU. Moreover, peripherin 2 is clearly detectable in healthy RPE due to both phagocytosis and the expression by the RPE cells themselves. Our novel findings are very promising for better understanding the molecular mechanisms taking place on RPE in uveitis. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 1398 KiB

Open AccessArticle

Budesonide-Loaded Guar Gum Microspheres for Colon Delivery: Preparation, Characterization and in Vitro/in Vivo Evaluation

by Ye Liu and Hong Zhou^*

Department of Gastroenterology Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China

Int. J. Mol. Sci. 2015, 16(2), 2693-2704; https://doi.org/10.3390/ijms16022693 - 26 Jan 2015

Cited by 26 | Viewed by 6238

Abstract

A novel budesonide (BUD) colon delivery release system was developed by using a natural polysaccharide, guar gum. The rigidity of the microspheres was induced by a chemical cross-linking method utilizing glutaraldehyde as the cross-linker. The mean particle size of the microspheres prepared was [...] Read more.

A novel budesonide (BUD) colon delivery release system was developed by using a natural polysaccharide, guar gum. The rigidity of the microspheres was induced by a chemical cross-linking method utilizing glutaraldehyde as the cross-linker. The mean particle size of the microspheres prepared was found to be 15.21 ± 1.32 µm. The drug loading and entrapment efficiency of the formulation were 17.78% ± 2.31% and 81.6% ± 5.42%, respectively. The microspheres were spherical in shape with a smooth surface, and the size was uniform. The in vitro release profiles indicated that the release of BUD from the microspheres exhibited a sustained release behavior. The model that fitted best for BUD released from the microspheres was the Higuchi kinetic model with a correlation coefficient r = 0.9993. A similar phenomenon was also observed in a pharmacokinetic study. The prolongation of the half-life (t_1/2), enhanced residence time (mean residence time, MRT) and decreased total clearance (CL) indicated that BUD microspheres could prolong the acting time of BUD in vivo. In addition, BUD guar gum microspheres are thought to have the potential to maintain BUD concentration within target ranges for a long time, decreasing the side effects caused by concentration fluctuation, ensuring the efficiency of treatment and improving patient compliance by reducing dosing frequency. None of the severe signs, like the appearance of epithelial necrosis and the sloughing of epithelial cells, were detected. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 969 KiB

Open AccessArticle

Sustainable Hydrogen Photoproduction by Phosphorus-Deprived Marine Green Microalgae Chlorella sp.

by Khorcheska Batyrova^1,2,*, Anastasia Gavrisheva¹, Elena Ivanova¹, Jianguo Liu³ and Anatoly Tsygankov¹

¹ Institute of Basic Biological Problems RAS, Institutskaya 2, Pushchino, Moscow Region 142290, Russia

² Microbiologie, Infectiologie et immunologie, Université de Montréal, CP 6128 Succursale Centre-ville, Montréal, QC H3C 3J7, Canada

³ Institute of Oceanology, Chinese Academy of Sciences, Chinese Academy of Sciences, 7 Nanhai Road, Qingdao 266071, China

Int. J. Mol. Sci. 2015, 16(2), 2705-2716; https://doi.org/10.3390/ijms16022705 - 26 Jan 2015

Cited by 69 | Viewed by 7622

Abstract

Previously it has been shown that green microalga Chlamydomonas reinhardtii is capable of prolonged H₂ photoproduction when deprived of sulfur. In addition to sulfur deprivation (-S), sustained H₂ photoproduction in C. reinhardtii cultures can be achieved under phosphorus-deprived (-P) conditions. Similar [...] Read more.

Previously it has been shown that green microalga Chlamydomonas reinhardtii is capable of prolonged H₂ photoproduction when deprived of sulfur. In addition to sulfur deprivation (-S), sustained H₂ photoproduction in C. reinhardtii cultures can be achieved under phosphorus-deprived (-P) conditions. Similar to sulfur deprivation, phosphorus deprivation limits O₂ evolving activity in algal cells and causes other metabolic changes that are favorable for H₂ photoproduction. Although significant advances in H₂ photoproduction have recently been realized in fresh water microalgae, relatively few studies have focused on H₂ production in marine green microalgae. In the present study phosphorus deprivation was applied for hydrogen production in marine green microalgae Chlorella sp., where sulfur deprivation is impossible due to a high concentration of sulfates in the sea water. Since resources of fresh water on earth are limited, the possibility of hydrogen production in seawater is more attractive. In order to achieve H₂ photoproduction in P-deprived marine green microalgae Chlorella sp., the dilution approach was applied. Cultures diluted to about 0.5–1.8 mg Chl·L⁻¹ in the beginning of P-deprivation were able to establish anaerobiosis, after the initial growth period, where cells utilize intracellular phosphorus, with subsequent transition to H₂ photoproduction stage. It appears that marine microalgae during P-deprivation passed the same stages of adaptation as fresh water microalgae. The presence of inorganic carbon was essential for starch accumulation and subsequent hydrogen production by microalgae. The H₂ accumulation was up to 40 mL H₂ gas per 1iter of the culture, which is comparable to that obtained in P-deprived C. reinhardtii culture. Full article

(This article belongs to the Special Issue Photosynthesis and Biological Hydrogen Production)

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15 pages, 12919 KiB

Open AccessArticle

Myricanol Induces Apoptotic Cell Death and Anti-Tumor Activity in Non-Small Cell Lung Carcinoma in Vivo

by Guanhai Dai^1,2,*,†, Yeling Tong^1,†, Xuan Chen¹, Zeming Ren¹, Xuhua Ying², Feng Yang¹ and Kequn Chai^2,3,*

¹ Institute of Basic Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou 310007, China

² Institute of Cancer Research, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou 310007, China

³ Oncology Department, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 2717-2731; https://doi.org/10.3390/ijms16022717 - 26 Jan 2015

Cited by 19 | Viewed by 7821

Abstract

This study explored the inhibiting effect and mechanism of myricanol on lung adenocarcinoma A549 xenografts in nude mice. Forty nude mice with subcutaneous A549 xenografts were randomly divided into five groups: high-dose myricanol (40 mg/kg body weight) group; middle-dose myricanol (20 mg/kg body [...] Read more.

This study explored the inhibiting effect and mechanism of myricanol on lung adenocarcinoma A549 xenografts in nude mice. Forty nude mice with subcutaneous A549 xenografts were randomly divided into five groups: high-dose myricanol (40 mg/kg body weight) group; middle-dose myricanol (20 mg/kg body weight) group; low-dose myricanol (10 mg/kg body weight) group; polyethylene glycol 400 vehicle group (1 mL/kg); and tumor model group. Nude mice were sacrificed after 14 days of treatment and the tumor inhibition rate (TIR, %) was then calculated. The relative mRNA expression levels of Bax, Bcl-2, VEGF, HIF-1α, and survivin in the tumor tissues were determined by real-time PCR. TUNEL assay was applied to determine cellular apoptosis, while IHC test was performed to detect the protein expression levels of Bax, Bcl-2, VEGF, HIF-1α, and survivin. The TIR of the three myricanol-treated groups ranged from 14.9% to 38.5%. The IHC results showed that the protein expression of Bcl-2, VEGF, HIF-1α, and survivin were consistently downregulated, whereas that of Bax was upregulated after myricanol treatment. Myricanol also significantly upregulated the mRNA expression of Bax and downregulated that of Bcl-2, VEGF, HIF-1α, and survivin in a dose-dependent manner (p < 0.05 to 0.001). These results are consistent with those of IHC. The TUNEL assay results indicated that apoptotic-positive cells significantly increased in the myricanol-treated tumor tissues compared with the cells of the vehicle control group (p < 0.01 to 0.001). These data suggest that myricanol could significantly decelerate tumor growth in vivo by inducing apoptosis. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables)

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15 pages, 702 KiB

Open AccessArticle

The Association of ADORA2A and ADORA2B Polymorphisms with the Risk and Severity of Chronic Heart Failure: A Case-Control Study of a Northern Chinese Population

by Ya-Jing Zhai^1,†, Ping Liu^2,†, Hai-Rong He¹, Xiao-Wei Zheng¹, Yan Wang¹, Qian-Ting Yang¹, Ya-Lin Dong^1,* and Jun Lu^1,*

¹ Department of Pharmacy, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China

² Department of Cardiovascular Medicine, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 2732-2746; https://doi.org/10.3390/ijms16022732 - 26 Jan 2015

Cited by 19 | Viewed by 6292

Abstract

The causes of chronic heart failure (CHF) and its progression are likely to be due to complex genetic factors. Adenosine receptors A2A and A2B (ADORA2A and ADORA2B, respectively) play an important role in cardio-protection. Therefore, polymorphisms in the genes encoding those receptors may [...] Read more.

The causes of chronic heart failure (CHF) and its progression are likely to be due to complex genetic factors. Adenosine receptors A2A and A2B (ADORA2A and ADORA2B, respectively) play an important role in cardio-protection. Therefore, polymorphisms in the genes encoding those receptors may affect the risk and severity of CHF. This study was a case-control comparative investigation of 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls. Four common single-nucleotide polymorphisms (SNPs) of ADORA2A (rs2236625, rs2236624, rs4822489, and rs5751876) and one SNP of ADORA2B (rs7208480) were genotyped and an association between SNPs and clinical outcomes was evaluated. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. The rs4822489 was significantly associated with the severity of CHF after adjustment for traditional cardiovascular risk factors (p = 0.040, OR = 1.912, 95% CI = 1.029–3.550). However, the five SNPs as well as the haplotypes were not found to be associated with CHF susceptibility. The findings of this study suggest that rs4822489 may contribute to the severity of CHF in the northern Chinese. However, further studies performed in larger populations and aimed at better defining the role of this gene are required. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

20 pages, 9089 KiB

Open AccessArticle

Binding Mode Analysis of Zerumbone to Key Signal Proteins in the Tumor Necrosis Factor Pathway

by Ayesha Fatima^1,2,*, Ahmad Bustamam Hj. Abdul¹, Rasedee Abdullah^1,3, Roghayeh Abedi Karjiban^4,5 and Vannajan Sanghiran Lee^6,*

¹ UPM-MAKNA Cancer Research Laboratory, Institute of Biosciences, University Putra Malaysia, 43400 Serdang, Malaysia

² Faculty of Pharmaceutical Sciences, UCSI University, 1-Jalan Menara Gading, Taman Connaught, Cheras, 56000 Kuala Lumpur, Malaysia

³ Department of Microbiology and Pathology, Faculty of Veterinary Medicine, University Putra Malaysia, 43400 Serdang, Malaysia

⁴ Department of Chemistry, Faculty of Science, University Putra Malaysia, 43400 Serdang, Malaysia

⁵ Enzyme and Microbial Technology Research Centre, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 Selangor, Malaysia

⁶ Department of Chemistry, Faculty of Science, University Malaya, Petaling Jaya, 50603 Selangor, Malaysia

Int. J. Mol. Sci. 2015, 16(2), 2747-2766; https://doi.org/10.3390/ijms16022747 - 26 Jan 2015

Cited by 26 | Viewed by 9358

Abstract

Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF) α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway [...] Read more.

Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF) α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway initiated by the binding of the protein to its receptor. Zerumbone, an active constituent of Zingiber zerumbet, Smith, is known to act on the tumor necrosis factor pathway upregulating tumour necrosis factor related apoptosis inducing ligand (TRAIL) death receptors and inducing apoptosis in cancer cells. Zerumbone is a sesquiterpene that is able to penetrate into the hydrophobic pockets of proteins to exert its inhibiting activity with several proteins. We found a good binding with the tumor necrosis factor, kinase κB (IKKβ) and the Nuclear factor κB (NF-κB) component proteins along the TNF pathway. Our results suggest that zerumbone can exert its apoptotic activities by inhibiting the cytoplasmic proteins. It inhibits the IKKβ kinase that activates the NF-κB and also binds to the NF-κB complex in the TNF pathway. Blocking both proteins can lead to inhibition of cell proliferating proteins to be downregulated and possibly ultimate induction of apoptosis. Full article

(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)

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27 pages, 2757 KiB

Open AccessArticle

Molecular Characterization of Three Gonadotropin Subunits and Their Expression Patterns during Ovarian Maturation in Cynoglossus semilaevis

by Bao Shi, Xuezhou Liu^*, Yongjiang Xu and Shanshan Wang

Qingdao Key Laboratory for Marine Fish Breeding and Biotechnology, Key Laboratory of Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, Shandong, China

Int. J. Mol. Sci. 2015, 16(2), 2767-2793; https://doi.org/10.3390/ijms16022767 - 27 Jan 2015

Cited by 22 | Viewed by 7194

Abstract

The endocrine regulation of reproduction in a multiple spawning flatfish with an ovary of asynchronous development remains largely unknown. The objectives of this study were to monitor changes in mRNA expression patterns of three gonadotropin hormone (GTH) subunits (FSHβ, LHβ and CGα) and [...] Read more.

The endocrine regulation of reproduction in a multiple spawning flatfish with an ovary of asynchronous development remains largely unknown. The objectives of this study were to monitor changes in mRNA expression patterns of three gonadotropin hormone (GTH) subunits (FSHβ, LHβ and CGα) and plasma GTH levels during ovarian maturation of half-smooth tongue sole Cynoglossus semilaevis. Cloning and sequence analysis revealed that the cDNAs of FSHβ, LHβ and CGα were 541, 670 and 685 bp in length, and encode for peptides of 130, 158 and 127 amino acids, respectively. The number of cysteine residues and potential N-linked glycosylation sites of the flatfish GTHs were conserved among teleosts. However, the primary structure of GTHs in Pleuronectiformes appeared to be highly divergent. The FSHβ transcriptional level in the pituitary remained high during the vitellogenic stage while plasma levels of FSH peaked and oocyte development was stimulated. The LHβ expression in the pituitary and ovary reached the maximum level during oocyte maturation stages when the plasma levels of LH peaked. The brain GTHs were expressed at the different ovarian stages. These results suggested that FSH and LH may simultaneously regulate ovarian development and maturation through the brain-pituitary-ovary axis endocrine system in tongue sole. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 1666 KiB

Open AccessArticle

In Vitro Selection of Single-Stranded DNA Molecular Recognition Elements against S. aureus Alpha Toxin and Sensitive Detection in Human Serum

by Ka L. Hong¹, Luisa Battistella¹, Alysia D. Salva¹, Ryan M. Williams^1,2 and Letha J. Sooter^1,*

¹ Department of Pharmaceutical Sciences, West Virginia University, 1 Medical Center Drive, P.O. Box 9530, Morgantown, WV 26506, USA

² Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry, 1275 York Avenue, P.O. Box 425, New York, NY 10065, USA

Int. J. Mol. Sci. 2015, 16(2), 2794-2809; https://doi.org/10.3390/ijms16022794 - 27 Jan 2015

Cited by 23 | Viewed by 7870

Abstract

Alpha toxin is one of the major virulence factors secreted by Staphylococcus aureus, a bacterium that is responsible for a wide variety of infections in both community and hospital settings. Due to the prevalence of S. aureus related infections and the emergence [...] Read more.

Alpha toxin is one of the major virulence factors secreted by Staphylococcus aureus, a bacterium that is responsible for a wide variety of infections in both community and hospital settings. Due to the prevalence of S. aureus related infections and the emergence of methicillin-resistant S. aureus, rapid and accurate diagnosis of S. aureus infections is crucial in benefiting patient health outcomes. In this study, a rigorous Systematic Evolution of Ligands by Exponential Enrichment (SELEX) variant previously developed by our laboratory was utilized to select a single-stranded DNA molecular recognition element (MRE) targeting alpha toxin with high affinity and specificity. At the end of the 12-round selection, the selected MRE had an equilibrium dissociation constant (K_d) of 93.7 ± 7.0 nM. Additionally, a modified sandwich enzyme-linked immunosorbent assay (ELISA) was developed by using the selected ssDNA MRE as the toxin-capturing element and a sensitive detection of 200 nM alpha toxin in undiluted human serum samples was achieved. Full article

(This article belongs to the Section Molecular Recognition)

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14 pages, 676 KiB

Open AccessReview

Detection of miRNA as Non-Invasive Biomarkers of Colorectal Cancer

by Albert Ren^1,2, Yujuan Dong^1,3, Ho Tsoi¹ and Jun Yu^1,*

¹ Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China

² Weinberg College of Arts and Sciences, Northwestern University, 633 Clark Street, Evanston, IL 60208, USA

³ Division of Colorectal Surgery, Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China

Int. J. Mol. Sci. 2015, 16(2), 2810-2823; https://doi.org/10.3390/ijms16022810 - 27 Jan 2015

Cited by 74 | Viewed by 8623

Abstract

Colorectal Cancer (CRC) is one of the deadliest cancers—ranking as the fourth most common cause of cancer-related deaths in the world. It is such a deadly disease because it is largely asymptomatic until the latter stages—oftentimes when the cancer has metastasized. Thus, a [...] Read more.

Colorectal Cancer (CRC) is one of the deadliest cancers—ranking as the fourth most common cause of cancer-related deaths in the world. It is such a deadly disease because it is largely asymptomatic until the latter stages—oftentimes when the cancer has metastasized. Thus, a huge emphasis of cancer treatment is placed on early detection. Currently, there is a lack of a noninvasive, reliable, and cost-effective screening method for CRC. In recent years, microRNA (miRNA) diagnostic markers have been suggested as a viable new screening method for CRC. miRNAs play an important role in carcinogenesis, and has been observed to be dysregulated in many cancers including CRC. This review examines the diagnostic potential of circulatory and fecal miRNA markers in relation to CRC, as well as current techniques to detect them. Full article

(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)

15 pages, 1087 KiB

Open AccessArticle

Probing Peptide and Protein Insertion in a Biomimetic S-Layer Supported Lipid Membrane Platform

by Samar Damiati^1,2

, Angelika Schrems^1,†, Eva-Kathrin Sinner¹

, Uwe B. Sleytr³ and Bernhard Schuster^1,*

¹ Institute for Synthetic Bioarchitectures, Department of NanoBiotechnology, University of Natural Resources and Life Sciences, Muthgasse 11, Vienna 1190, Austria

² Department of Biochemistry, King Abdulaziz University, Jeddah 21465, Saudi Arabia

³ Institute for Biophysics, Department of NanoBiotechnology, University of Natural Resources and Life Sciences, Muthgasse 11, Vienna 1190, Austria

^† Present address: Sysmex Austria GmbH, Odoakergasse 34-36, Vienna 1160, Austria

Int. J. Mol. Sci. 2015, 16(2), 2824-2838; https://doi.org/10.3390/ijms16022824 - 27 Jan 2015

Cited by 14 | Viewed by 6793

Abstract

The most important aspect of synthetic lipid membrane architectures is their ability to study functional membrane-active peptides and membrane proteins in an environment close to nature. Here, we report on the generation and performance of a biomimetic platform, the S-layer supported lipid membrane [...] Read more.

The most important aspect of synthetic lipid membrane architectures is their ability to study functional membrane-active peptides and membrane proteins in an environment close to nature. Here, we report on the generation and performance of a biomimetic platform, the S-layer supported lipid membrane (SsLM), to investigate the structural and electrical characteristics of the membrane-active peptide gramicidin and the transmembrane protein α-hemolysin in real-time using a quartz crystal microbalance with dissipation monitoring in combination with electrochemical impedance spectroscopy. A shift in membrane resistance is caused by the interaction of α-hemolysin and gramicidin with SsLMs, even if only an attachment onto, or functional channels through the lipid membrane, respectively, are formed. Moreover, the obtained results did not indicate the formation of functional α-hemolysin pores, but evidence for functional incorporation of gramicidin into this biomimetic architecture is provided. Full article

(This article belongs to the Special Issue Membrane Protein Based Biosensors)

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12 pages, 742 KiB

Open AccessArticle

Combined Toxic Effects of Heavy Metals and Antibiotics on a Pseudomonas fluorescens Strain ZY2 Isolated from Swine Wastewater

by Yan Zhou, Yan-Bin Xu^*, Jia-Xin Xu, Xiao-Hua Zhang, Shi-Hui Xu and Qing-Ping Du

School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China

Int. J. Mol. Sci. 2015, 16(2), 2839-2850; https://doi.org/10.3390/ijms16022839 - 27 Jan 2015

Cited by 56 | Viewed by 8326

Abstract

A Pseudomonas fluorescens strain ZY2, isolated from swine wastewater, was used to investigate the synergistic effects of five heavy metals (Pb, Cu, Zn, Cr(VI) and Hg) on bacterial resistance to antibiotics. Results indicate that the combined effects of antibiotic type, heavy metal type [...] Read more.

A Pseudomonas fluorescens strain ZY2, isolated from swine wastewater, was used to investigate the synergistic effects of five heavy metals (Pb, Cu, Zn, Cr(VI) and Hg) on bacterial resistance to antibiotics. Results indicate that the combined effects of antibiotic type, heavy metal type and concentration were significant (p < 0.01). Cross-resistance to Hg and antibiotics was the most noticeable. Moreover, the resistance to Hg and cefradine or amoxicillin, and Cr and amoxicillin were synergistic for low heavy metal concentrations, and turned antagonistic with increasing concentrations, while the resistances to Cr or Cu and cefradine, Pb or Cu and amoxicillin, Cu and norfloxacin showed reverse effects. In addition, resistance to Zn and amoxicillin were always synergetic, while resistance to Pb and cefradine or norfloxacin, Cr or Hg and norfloxacin as well as all the heavy metals and tetracycline were antagonistic. These results indicate that bacterial resistance to antibiotics can be affected by the type and concentration of co-exposed heavy metals and may further threaten people’s health and ecological security severely via horizontal gene transfer. Full article

(This article belongs to the Special Issue Microbial Metabolism of Toxic Organic Pollutants and Transformation of Metals/Metalloids and Ecotoxicity Assessment)

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13 pages, 1101 KiB

Open AccessReview

Interleukin-27 in T Cell Immunity

by Yukiko Iwasaki¹, Keishi Fujio^1,*, Tomohisa Okamura^1,2 and Kazuhiko Yamamoto¹

¹ Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

² Max Planck-The University of Tokyo Center for Integrative Inflammology, the University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan

Int. J. Mol. Sci. 2015, 16(2), 2851-2863; https://doi.org/10.3390/ijms16022851 - 27 Jan 2015

Cited by 87 | Viewed by 10989

Abstract

Interleukin (IL)-27, a member of IL-12/IL-23 heterodimeric family of cytokines, has pleiotropic properties that can enhance or limit immune responses. IL-27 acts on various cell types, including T cells, B cells, macrophages, dendritic cells, natural killer (NK) cells and non-hematopoietic cells. Intensive studies [...] Read more.

Interleukin (IL)-27, a member of IL-12/IL-23 heterodimeric family of cytokines, has pleiotropic properties that can enhance or limit immune responses. IL-27 acts on various cell types, including T cells, B cells, macrophages, dendritic cells, natural killer (NK) cells and non-hematopoietic cells. Intensive studies have been conducted especially on T cells, revealing that various subsets of T cells respond uniquely to IL-27. IL-27 induces expansion of Th1 cells by activating signal transducer and activator of transcription (STAT) 1-mediated T-bet signaling pathway. On the other hand, IL-27 suppresses immune responses through inhibition of the development of T helper (Th) 17 cells and induction of IL-10 production in a STAT1- and STAT3-dependent manner. IL-27 is a potentially promising cytokine for therapeutic approaches on various human diseases. Here, we provide an overview of the biology of IL-27 related to T cell subsets, its structure, and production mechanism. Full article

(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)

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15 pages, 1118 KiB

Open AccessArticle

Profiling of Fatty Acids Composition in Suet Oil Based on GC–EI-qMS and Chemometrics Analysis

by Jun Jiang^1,2 and Xiaobin Jia^1,2,*

¹ Affiliated Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Xianlin Avenue 138#, Xianlin University City, Nanjing 210023, China

² Key Laboratory of New Drug Delivery System of Chinese Meteria Medica, Jiangsu Provincial Academy of Chinese Medicine, 100# Shizi Road, Nanjing 210028, China

Int. J. Mol. Sci. 2015, 16(2), 2864-2878; https://doi.org/10.3390/ijms16022864 - 28 Jan 2015

Cited by 8 | Viewed by 7671

Abstract

Fatty acid (FA) composition of suet oil (SO) was measured by precolumn methylesterification (PME) optimized using a Box–Behnken design (BBD) and gas chromatography/electron ionization-quadrupole mass spectrometry (GC–EI-qMS). A spectral library (NIST 08) and standard compounds were used to identify FAs in SO representing [...] Read more.

Fatty acid (FA) composition of suet oil (SO) was measured by precolumn methylesterification (PME) optimized using a Box–Behnken design (BBD) and gas chromatography/electron ionization-quadrupole mass spectrometry (GC–EI-qMS). A spectral library (NIST 08) and standard compounds were used to identify FAs in SO representing 90.89% of the total peak area. The ten most abundant FAs were derivatized into FA methyl esters (FAMEs) and quantified by GC–EI-qMS; the correlation coefficient of each FAME was 0.999 and the lowest concentration quantified was 0.01 μg/mL. The range of recovery of the FAMEs was 82.1%–98.7% (relative standard deviation 2.2%–6.8%). The limits of quantification (LOQ) were 1.25–5.95 μg/L. The number of carbon atoms in the FAs identified ranged from 12 to 20; hexadecanoic and octadecanoic acids were the most abundant. Eighteen samples of SO purchased from Qinghai, Anhui and Jiangsu provinces of China were categorized into three groups by principal component analysis (PCA) according to the contents of the most abundant FAs. The results showed SOs samples were rich in FAs with significantly different profiles from different origins. The method described here can be used for quality control and SO differentiation on the basis of the FA profile. Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

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14 pages, 801 KiB

Open AccessReview

BRCA1 and p53 Tumor Suppressor Molecules in Alzheimer’s Disease

by Atsuko Nakanishi^†, Akari Minami, Yasuko Kitagishi, Yasunori Ogura and Satoru Matsuda^*,†

¹ Department of Food Science and Nutrition, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan

^† These authors are equally contributed to this work.

Int. J. Mol. Sci. 2015, 16(2), 2879-2892; https://doi.org/10.3390/ijms16022879 - 28 Jan 2015

Cited by 31 | Viewed by 15294

Abstract

Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimer’s disease. Alzheimer’s disease is the most common neurodegenerative disorder, however, the precise molecular events that control the [...] Read more.

Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimer’s disease. Alzheimer’s disease is the most common neurodegenerative disorder, however, the precise molecular events that control the death of neuronal cells are unclear. Recently, a fundamental role for tumor suppressor molecules in regulating neurons in Alzheimer’s disease was highlighted. Generally, onset of neurodegenerative diseases including Alzheimer’s disease may be delayed with use of dietary neuro-protective agents against oxidative stresses. Studies suggest that dietary antioxidants are also beneficial for brain health in reducing disease-risk and in slowing down disease-progression. We summarize research advances in dietary regulation for the treatment of Alzheimer’s disease with a focus on its modulatory roles in BRCA1 and p53 tumor suppressor expression, in support of further therapeutic research in this field. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)

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20 pages, 1978 KiB

Open AccessReview

Regulation of Human Adenovirus Alternative RNA Splicing by the Adenoviral L4-33K and L4-22K Proteins

by Roberta Biasiotto and Göran Akusjärvi^*

Department of Medical Biochemistry and Microbiology, Science for Life Laboratory Uppsala University, Uppsala 75123, Sweden

Int. J. Mol. Sci. 2015, 16(2), 2893-2912; https://doi.org/10.3390/ijms16022893 - 28 Jan 2015

Cited by 28 | Viewed by 10952

Abstract

Adenovirus makes extensive use of alternative RNA splicing to produce a complex set of spliced viral mRNAs. Studies aimed at characterizing the interactions between the virus and the host cell RNA splicing machinery have identified three viral proteins of special significance for the [...] Read more.

Adenovirus makes extensive use of alternative RNA splicing to produce a complex set of spliced viral mRNAs. Studies aimed at characterizing the interactions between the virus and the host cell RNA splicing machinery have identified three viral proteins of special significance for the control of late viral gene expression: L4-33K, L4-22K, and E4-ORF4. L4-33K is a viral alternative RNA splicing factor that controls L1 alternative splicing via an interaction with the cellular protein kinases Protein Kinase A (PKA) and DNA-dependent protein kinase (DNA-PK). L4-22K is a viral transcription factor that also has been implicated in the splicing of a subset of late viral mRNAs. E4-ORF4 is a viral protein that binds the cellular protein phosphatase IIA (PP2A) and controls Serine/Arginine (SR)-rich protein activity by inducing SR protein dephosphorylation. The L4-33K, and most likely also the L4-22K protein, are highly phosphorylated in vivo. Here we will review the function of these viral proteins in the post-transcriptional control of adenoviral gene expression and further discuss the significance of potential protein kinases phosphorylating the L4-33K and/or L4-22K proteins. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing)

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29 pages, 4407 KiB

Open AccessArticle

Systems Pharmacology Dissection of the Anti-Inflammatory Mechanism for the Medicinal Herb Folium Eriobotryae

by Jingxiao Zhang^1,†, Yan Li^1,*,†, Su-Shing Chen^2,3, Lilei Zhang⁴, Jinghui Wang¹, Yinfeng Yang¹, Shuwei Zhang¹, Yanqiu Pan^1,*, Yonghua Wang^5,* and Ling Yang⁶

¹ Key laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China

² System Biology Lab, University of Florida, Gainesville, FL 32608, USA

³ Department of Electrical and Computer Engineering, University of Florida, Gainesville, FL 32608, USA

⁴ School of Chemistry and Environmental Engineering, Hubei University for Nationalities, Enshi 445000, China

⁵ Center of Bioinformatics, College of Life Science, Northwest A&F University, Yangling 712100, China

⁶ Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 2913-2941; https://doi.org/10.3390/ijms16022913 - 28 Jan 2015

Cited by 44 | Viewed by 10532

Abstract

Inflammation is a hallmark of many diseases like diabetes, cancers, atherosclerosis and arthritis. Thus, lots of concerns have been raised toward developing novel anti-inflammatory agents. Many alternative herbal medicines possess excellent anti-inflammatory properties, yet their precise mechanisms of action are yet to be [...] Read more.

Inflammation is a hallmark of many diseases like diabetes, cancers, atherosclerosis and arthritis. Thus, lots of concerns have been raised toward developing novel anti-inflammatory agents. Many alternative herbal medicines possess excellent anti-inflammatory properties, yet their precise mechanisms of action are yet to be elucidated. Here, a novel systems pharmacology approach based on a large number of chemical, biological and pharmacological data was developed and exemplified by a probe herb Folium Eriobotryae, a widely used clinical anti-inflammatory botanic drug. The results show that 11 ingredients of this herb with favorable pharmacokinetic properties are predicted as active compounds for anti-inflammatory treatment. In addition, via systematic network analyses, their targets are identified to be 43 inflammation-associated proteins including especially COX2, ALOX5, PPARG, TNF and RELA that are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway, the rheumatoid arthritis pathway and NF-κB signaling pathway. All these demonstrate that the integrated systems pharmacology method provides not only an effective tool to illustrate the anti-inflammatory mechanisms of herbs, but also a new systems-based approach for drug discovery from, but not limited to, herbs, especially when combined with further experimental validations. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 1001 KiB

Open AccessReview

A Time to Kill: Targeting Apoptosis in Cancer

by Jean L. Koff, Sampath Ramachandiran and Leon Bernal-Mizrachi^*

Department of Hematology and Medical Oncology at the Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA

Int. J. Mol. Sci. 2015, 16(2), 2942-2955; https://doi.org/10.3390/ijms16022942 - 28 Jan 2015

Cited by 248 | Viewed by 16445

Abstract

The process of apoptosis is essential for maintaining the physiologic balance between cell death and cell growth. This complex process is executed by two major pathways that participate in activating an executioner mechanism leading to chromatin disintegration and nuclear fragmentation. Dysregulation of these [...] Read more.

The process of apoptosis is essential for maintaining the physiologic balance between cell death and cell growth. This complex process is executed by two major pathways that participate in activating an executioner mechanism leading to chromatin disintegration and nuclear fragmentation. Dysregulation of these pathways often contributes to cancer development and resistance to cancer therapy. Here, we review the most recent discoveries in apoptosis regulation and possible mechanisms for resensitizing tumor cells to therapy. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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15 pages, 1265 KiB

Open AccessArticle

Expression and Diagnostic Value of HE4 in Pancreatic Adenocarcinoma

by Tianhe Huang^1,2,†, Shi-Wen Jiang^2,3,†, Liangyi Qin^4,†, Christopher Senkowski³, Christian Lyle⁵, Karen Terry³, Steven Brower⁶, Haibin Chen⁷, Wayne Glasgow^2,3, Yongchang Wei^1,* and Jinping Li^2,3,8,*

¹ Department of Clinical Oncology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China

² Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA

³ Curtis and Elizabeth Anderson Cancer Institute, Department of Surgery, Memorial Health University Medical Center, Savannah, GA 31404, USA

⁴ Department of Clinical Laboratory, Shanghai YangSi Hospital, Shanghai 200135, China

⁵ Department of Biological Sciences, Savannah State University, Savannah, GA 31404, USA

⁶ Department of Surgery & Surgical Oncology, Mount Sinai Beth Israel Medical Center, New York, NY 10003, USA

⁷ Department of Histology and Embryology, Shantou University Medical College, Shantou 515041, China

⁸ Department of Obstetrics and Gynecology, Memorial Health University Medical Center, Savannah, GA 31404, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 2956-2970; https://doi.org/10.3390/ijms16022956 - 29 Jan 2015

Cited by 31 | Viewed by 7542

Abstract

Human epididymis protein 4 (HE4) is a recognized biomarker in ovarian and endometrial cancer and over-expressed in pancreatic adenocarcinoma. The diagnostic value of HE4 in pancreatic adenocarcinoma remains unknown. Here we elucidate mRNA, protein and serum level of HE4 in pancreatic adenocarcinoma. HE4 [...] Read more.

Human epididymis protein 4 (HE4) is a recognized biomarker in ovarian and endometrial cancer and over-expressed in pancreatic adenocarcinoma. The diagnostic value of HE4 in pancreatic adenocarcinoma remains unknown. Here we elucidate mRNA, protein and serum level of HE4 in pancreatic adenocarcinoma. HE4 mRNA level in tumor adjacent tissues and pancreatic adenocarcinoma tissues were tested by real time-PCR. Tissue microarray containing normal, adenocarcinoma, and adjacent pancreatic tissue was tested by immunohistochemistry (IHC). Serum level of HE4, carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3) and carbohydrate antigen 125 (CA125) were detected by ELISA assay in control and tumor patients. Further we compared the sensitivity and specificity of determining HE4, CA19-9, CA15-3, and CA125 for diagnosis of pancreatic adenocarcinoma and assessed the complementary diagnostic value of HE4, CA19-9, CA15-3 and CA125. Real time PCR showed significantly increased HE4 mRNA level in pancreatic adenocarcinoma compared with control. Result of IHC showed that HE4 significantly higher expressed in the human pancreatic carcinoma tissues than in both normal and adjacent non-tumorous pancreatic tissues, and the staining intensity is inversely correlated with the clinical stage. HE4 was highly expressed in early stage of pancreatic adenocarcinoma. Serum HE4 level is higher in cases with pancreatic adenocarcinoma than in the controls. Serum HE4 levels could research to a sensitivity of 45.83% and specificity of 93.75% when the Cutoff was set at 4.59 ng/mL. The Combined HE4 and CA19-9 increased the sensitivity to 83.33%; and interestingly, the combination of HE4 with CA15-3 led to the most powerful sensitivity of 87.5%. Combined with CA19-9 and CA15-3, HE4 could be a potential biomarker to improve the diagnostic power for pancreatic adenocarcinoma. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer and Its Role in Tailored Cancer Therapy)

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46 pages, 3217 KiB

Open AccessReview

Effects of Atmospheric Pressure Plasmas on Isolated and Cellular DNA—A Review

by Krishna Priya Arjunan¹, Virender K. Sharma² and Sylwia Ptasinska^1,3,4,*

¹ Radiation Laboratory, University of Notre Dame, Notre Dame, IN 46556, USA

² Department of Environmental and Occupational Health, School of Public Health, Texas A&M University, 1266 TAMU, College Station, TX 77843, USA

³ Department of Physics, University of Notre Dame, Notre Dame, IN 46556, USA

⁴ Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA

Int. J. Mol. Sci. 2015, 16(2), 2971-3016; https://doi.org/10.3390/ijms16022971 - 29 Jan 2015

Cited by 168 | Viewed by 13778

Abstract

Atmospheric Pressure Plasma (APP) is being used widely in a variety of biomedical applications. Extensive research in the field of plasma medicine has shown the induction of DNA damage by APP in a dose-dependent manner in both prokaryotic and eukaryotic systems. Recent evidence [...] Read more.

Atmospheric Pressure Plasma (APP) is being used widely in a variety of biomedical applications. Extensive research in the field of plasma medicine has shown the induction of DNA damage by APP in a dose-dependent manner in both prokaryotic and eukaryotic systems. Recent evidence suggests that APP-induced DNA damage shows potential benefits in many applications, such as sterilization and cancer therapy. However, in several other applications, such as wound healing and dentistry, DNA damage can be detrimental. This review reports on the extensive investigations devoted to APP interactions with DNA, with an emphasis on the critical role of reactive species in plasma-induced damage to DNA. The review consists of three main sections dedicated to fundamental knowledge of the interactions of reactive oxygen species (ROS)/reactive nitrogen species (RNS) with DNA and its components, as well as the effects of APP on isolated and cellular DNA in prokaryotes and eukaryotes. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)

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2 pages, 596 KiB

Open AccessCorrection

Correction: Wai, M.G.C., et al. A Review of Pinealectomy-Induced Melatonin-Deficient Animal Models for the Study of Etiopathogenesis of Adolescent Idiopathic Scoliosis. Int. J. Mol. Sci. 2014, 15, 16484–16499

by Gene Chi Wai Man¹, William Wei Jun Wang^2,3, Annie Po Yee Yim⁴, Jack Ho Wong⁵, Tzi Bun Ng⁵, Tsz Ping Lam⁴, Simon Kwong Man Lee⁶, Bobby Kin Wah Ng⁴, Chi Chiu Wang¹

, Yong Qiu^2,3 and Jack Chun Yiu Cheng^3,4,*

¹ Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

² Department of Spine Surgery, Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China

³ Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, Hong Kong, China

⁴ Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

⁵ School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

⁶ Lee Hysan Clinical Research Laboratory, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

Int. J. Mol. Sci. 2015, 16(2), 3017-3018; https://doi.org/10.3390/ijms16023017 - 29 Jan 2015

Cited by 2 | Viewed by 4964

Abstract

The authors wish to make the following corrections to this paper [1]: The first name and surname of the authors were reversed. It should be corrected in the following format (with the surname in bold text):[...] Full article

16 pages, 434 KiB

Open AccessArticle

Reactive Oxygen and Nitrogen Species in Defense/Stress Responses Activated by Chitosan in Sycamore Cultured Cells

by Massimo Malerba^1,* and Raffaella Cerana²

¹ Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, Piazza della Scienza 2, Milan 20126, Italy

² Dipartimento di Scienze dell'Ambiente e del Territorio e di Scienze della Terra, Università degli Studi di Milano-Bicocca, Piazza della Scienza 1, Milan 20126, Italy

Int. J. Mol. Sci. 2015, 16(2), 3019-3034; https://doi.org/10.3390/ijms16023019 - 29 Jan 2015

Cited by 39 | Viewed by 6197

Abstract

Chitosan (CHT) is a non-toxic and inexpensive compound obtained by deacetylation of chitin, the main component of the exoskeleton of arthropods as well as of the cell walls of many fungi. In agriculture CHT is used to control numerous diseases on various horticultural [...] Read more.

Chitosan (CHT) is a non-toxic and inexpensive compound obtained by deacetylation of chitin, the main component of the exoskeleton of arthropods as well as of the cell walls of many fungi. In agriculture CHT is used to control numerous diseases on various horticultural commodities but, although different mechanisms have been proposed, the exact mode of action of CHT is still unknown. In sycamore (Acer pseudoplatanus L.) cultured cells, CHT induces a set of defense/stress responses that includes production of H₂O₂ and nitric oxide (NO). We investigated the possible signaling role of these reactive molecules in some CHT-induced responses by means of inhibitors of production and/or scavengers. The results show that both reactive nitrogen and oxygen species are not only a mere symptom of stress conditions but are involved in the responses induced by CHT in sycamore cells. In particular, NO appears to be involved in a cell death form induced by CHT that shows apoptotic features like DNA fragmentation, increase in caspase-3-like activity and release of cytochrome c from the mitochondrion. On the contrary, reactive oxygen species (ROS) appear involved in a cell death form induced by CHT that does not show these apoptotic features but presents increase in lipid peroxidation. Full article

(This article belongs to the Special Issue Abiotic Stress and Gene Networks in Plants)

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23 pages, 1751 KiB

Open AccessArticle

Transcriptome Analysis of Methyl Jasmonate-Elicited Panax ginseng Adventitious Roots to Discover Putative Ginsenoside Biosynthesis and Transport Genes

by Hongzhe Cao, Mohammed Nuruzzaman, Hao Xiu, Jingjia Huang, Kunlu Wu, Xianghui Chen, Jijia Li, Li Wang, Ji-Hak Jeong, Sun-Jin Park, Fang Yang, Junli Luo and Zhiyong Luo^*

Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China

Int. J. Mol. Sci. 2015, 16(2), 3035-3057; https://doi.org/10.3390/ijms16023035 - 29 Jan 2015

Cited by 58 | Viewed by 9045

Abstract

The Panax ginseng C.A. Meyer belonging to the Araliaceae has long been used as an herbal medicine. Although public databases are presently available for this family, no methyl jasmonate (MeJA) elicited transcriptomic information was previously reported on this species, with the exception of [...] Read more.

The Panax ginseng C.A. Meyer belonging to the Araliaceae has long been used as an herbal medicine. Although public databases are presently available for this family, no methyl jasmonate (MeJA) elicited transcriptomic information was previously reported on this species, with the exception of a few expressed sequence tags (ESTs) using the traditional Sanger method. Here, approximately 53 million clean reads of adventitious root transcriptome were separately filtered via Illumina HiSeq™2000 from two samples treated with MeJA (Pg-MeJA) and equal volumes of solvent, ethanol (Pg-Con). Jointly, a total of 71,095 all-unigenes from both samples were assembled and annotated, and based on sequence similarity search with known proteins, a total of 56,668 unigenes was obtained. Out of these annotated unigenes, 54,920 were assigned to the NCBI non-redundant protein (Nr) database, 35,448 to the Swiss-prot database, 43,051 to gene ontology (GO), and 19,986 to clusters of orthologous groups (COG). Searching in the Kyoto encyclopedia of genes and genomes (KEGG) pathway database indicated that 32,200 unigenes were mapped to 128 KEGG pathways. Moreover, we obtained several genes showing a wide range of expression levels. We also identified a total of 749 ginsenoside biosynthetic enzyme genes and 12 promising pleiotropic drug resistance (PDR) genes related to ginsenoside transport. Full article

(This article belongs to the Special Issue Plant Molecular Biology)

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13 pages, 2634 KiB

Open AccessArticle

A Ribosomal Protein AgRPS3aE from Halophilic Aspergillus glaucus Confers Salt Tolerance in Heterologous Organisms

by Xilong Liang^1,2,†, Yiling Liu^1,†, Lixia Xie¹, Xiaodan Liu¹, Yi Wei¹, Xiaoyang Zhou¹ and Shihong Zhang^1,*

¹ College of Plant Sciences, Jilin University, Changchun 130062, China

² Agricultural College, Heilongjiang Bayi Agricultural University, Daqing 163319, China

^† These authors are equally contributed to this work.

Int. J. Mol. Sci. 2015, 16(2), 3058-3070; https://doi.org/10.3390/ijms16023058 - 29 Jan 2015

Cited by 27 | Viewed by 7258

Abstract

High salt in soils is one of the abiotic stresses that significantly reduces crop yield, although saline lands are considered potential resources arable for agriculture. Currently, genetic engineering for enhancing salt tolerance is being tested as an efficient and viable strategy for crop [...] Read more.

High salt in soils is one of the abiotic stresses that significantly reduces crop yield, although saline lands are considered potential resources arable for agriculture. Currently, genetic engineering for enhancing salt tolerance is being tested as an efficient and viable strategy for crop improvement. We previously characterized a large subunit of the ribosomal protein RPL44, which is involved in osmotic stress in the extremely halophilic fungus Aspergillus glaucus. Here, we screened another ribosomal protein (AgRPS3aE) that also produced high-salt tolerance in yeast. Bioinformatics analysis indicated that AgRPS3aE encodes a 29.2 kDa small subunit of a ribosomal protein belonging to the RPS3Ae family in eukaryotes. To further confirm its protective function against salinity, we expressed AgRPS3aE in three heterologous systems, the filamentous fungus Magnaporthe oryzae and two model plants Arabidopsis and tobacco. Overexpression of AgRPS3aE in all tested transformants significantly alleviated stress symptoms compared with controls, suggesting that AgRPS3aE functions not only in fungi but also in plants. Considering that ribosomal proteins are housekeeping components in organisms from prokaryotes to eukaryotes, we propose that AgRPS3aE is one of the optimal genes for improving high-salt tolerance in crops. Full article

(This article belongs to the Special Issue Abiotic Stress and Gene Networks in Plants)

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24 pages, 3852 KiB

Open AccessReview

Pacemaker Activity of the Human Sinoatrial Node: An Update on the Effects of Mutations in HCN4 on the Hyperpolarization-Activated Current

by Arie O. Verkerk

and Ronald Wilders^*

Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

Int. J. Mol. Sci. 2015, 16(2), 3071-3094; https://doi.org/10.3390/ijms16023071 - 29 Jan 2015

Cited by 93 | Viewed by 11823

Abstract

Since 2003, several loss-of-function mutations in the HCN4 gene, which encodes the HCN4 protein, have been associated with sinus node dysfunction. In human sinoatrial node (SAN), HCN4 is the most abundant of the four isoforms of the HCN family. Tetramers of HCN subunits [...] Read more.

Since 2003, several loss-of-function mutations in the HCN4 gene, which encodes the HCN4 protein, have been associated with sinus node dysfunction. In human sinoatrial node (SAN), HCN4 is the most abundant of the four isoforms of the HCN family. Tetramers of HCN subunits constitute the ion channels that conduct the hyperpolarization-activated “funny” current (I_f), which plays an important modulating role in SAN pacemaker activity. Voltage-clamp experiments on HCN4 channels expressed in COS-7, CHO and HEK-293 cells, as well as in Xenopus oocytes have revealed changes in the expression and kinetics of mutant channels, but the extent to which especially the kinetic changes would affect I_f flowing during a human SAN action potential often remains unresolved. In our contribution to the Topical Collection on Human Single Nucleotide Polymorphisms and Disease Diagnostics, we provide an updated review of the mutation-induced changes in the expression and kinetics of HCN4 channels and provide an overview of their effects on I_f during the time course of a human SAN action potential, as assessed in simulated action potential clamp experiments. Future research may solve apparent inconsistencies between data from clinical studies and data from in vitro and in silico experiments. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

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21 pages, 894 KiB

Open AccessReview

Neuron Membrane Trafficking and Protein Kinases Involved in Autism and ADHD

by Yasuko Kitagishi^†, Akari Minami^†, Atsuko Nakanishi^†, Yasunori Ogura and Satoru Matsuda^*,†

¹ Department of Food Science and Nutrition, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3095-3115; https://doi.org/10.3390/ijms16023095 - 30 Jan 2015

Cited by 33 | Viewed by 10508

Abstract

A brain-enriched multi-domain scaffolding protein, neurobeachin has been identified as a candidate gene for autism patients. Mutations in the synaptic adhesion protein cell adhesion molecule 1 (CADM1) are also associated with autism spectrum disorder, a neurodevelopmental disorder of uncertain molecular origin. Potential roles [...] Read more.

A brain-enriched multi-domain scaffolding protein, neurobeachin has been identified as a candidate gene for autism patients. Mutations in the synaptic adhesion protein cell adhesion molecule 1 (CADM1) are also associated with autism spectrum disorder, a neurodevelopmental disorder of uncertain molecular origin. Potential roles of neurobeachin and CADM1 have been suggested to a function of vesicle transport in endosomal trafficking. It seems that protein kinase B (AKT) and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) have key roles in the neuron membrane trafficking involved in the pathogenesis of autism. Attention deficit hyperactivity disorder (ADHD) is documented to dopaminergic insufficiencies, which is attributed to synaptic dysfunction of dopamine transporter (DAT). AKT is also essential for the DAT cell-surface redistribution. In the present paper, we summarize and discuss the importance of several protein kinases that regulate the membrane trafficking involved in autism and ADHD, suggesting new targets for therapeutic intervention. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 813 KiB

Open AccessArticle

Optimization of Influential Nutrients during Direct Cellulose Fermentation into Hydrogen by Clostridium thermocellum

by Rumana Islam¹, Richard Sparling², Nazim Cicek¹ and David B. Levin^1,*

¹ Department of Biosystems Engineering, University of Manitoba, Winnipeg, MB R3T 2N2, Canada

² Department of Microbiology, University of Manitoba, Winnipeg, MB R3T 2N2, Canada

Int. J. Mol. Sci. 2015, 16(2), 3116-3132; https://doi.org/10.3390/ijms16023116 - 30 Jan 2015

Cited by 27 | Viewed by 6184

Abstract

Combinatorial effects of influential growth nutrients were investigated in order to enhance hydrogen (H₂) production during direct conversion of cellulose by Clostridium thermocellum DSM 1237. A central composite face-centered design and response surface methodology (RSM) were applied to optimize concentrations of [...] Read more.

Combinatorial effects of influential growth nutrients were investigated in order to enhance hydrogen (H₂) production during direct conversion of cellulose by Clostridium thermocellum DSM 1237. A central composite face-centered design and response surface methodology (RSM) were applied to optimize concentrations of cellulose, yeast extract (YE), and magnesium chloride (Mg) in culture. The overall optimum composition generated by the desirability function resulted in 57.28 mmol H₂/L-culture with 1.30 mol H₂/mol glucose and 7.48 mmol/(g·cell·h) when cultures contained 25 g/L cellulose, 2 g/L YE, and 1.75 g/L Mg. Compared with the unaltered medium, the optimized medium produced approximately 3.2-fold more H₂ within the same time-frame with 50% higher specific productivity, which are also better than previously reported values from similar studies. Nutrient composition that diverted carbon and electron flux away from H₂ promoting ethanol production was also determined. This study represents the first investigation dealing with multifactor optimization with RSM for H₂ production during direct cellulose fermentation. Full article

(This article belongs to the Special Issue Photosynthesis and Biological Hydrogen Production)

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15 pages, 1018 KiB

Open AccessReview

Heart Failure and Atrial Fibrillation: From Basic Science to Clinical Practice

by João Pedro Ferreira^1,2,* and Mário Santos^2,3

¹ Internal Medicine Department, Centro Hospitalar do Porto, Porto 4099-001, Portugal

² Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Porto 4200-319, Portugal

³ Cardiology Department, Centro Hospitalar do Porto, Porto 4099-001, Portugal

Int. J. Mol. Sci. 2015, 16(2), 3133-3147; https://doi.org/10.3390/ijms16023133 - 30 Jan 2015

Cited by 45 | Viewed by 13158

Abstract

Heart failure (HF) and atrial fibrillation (AF) are two growing epidemics associated with significant morbidity and mortality. They often coexist due to common risk factors and shared pathophysiological mechanisms. Patients presenting with both HF and AF have a worse prognosis and present a [...] Read more.

Heart failure (HF) and atrial fibrillation (AF) are two growing epidemics associated with significant morbidity and mortality. They often coexist due to common risk factors and shared pathophysiological mechanisms. Patients presenting with both HF and AF have a worse prognosis and present a particular therapeutic challenge to clinicians. This review aims to appraise the common pathophysiological background, as well as the prognostic and therapeutic implications of coexistent HF and AF. Full article

(This article belongs to the Special Issue Pathogenesis of Cardiac Arrhythmias and Heart Failure)

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15 pages, 2916 KiB

Open AccessArticle

The Regulation and Function of miR-21-FOXO3a-miR-34b/c Signaling in Breast Cancer

by Xiangyan Liu^1,2, Jie Feng³, Lili Tang², Liqiu Liao¹, Qing Xu⁴ and Shaihong Zhu^1,*

¹ Department of General Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China

² Department of Breast Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China

³ Department of Nursing, Thomas Jefferson University, Philadelphia, PA 19107, USA

⁴ Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA

Int. J. Mol. Sci. 2015, 16(2), 3148-3162; https://doi.org/10.3390/ijms16023148 - 30 Jan 2015

Cited by 54 | Viewed by 9079

Abstract

Upregulation of miR-21 (microRNA-21) and downregulation of miR-34b/c have been found in breast cancer (BC). However, their regulation mechanism and function roles in BC have not been fully addressed. Here, we report that miR-21 levels were inversely correlated with miR-34b/c levels in BC. [...] Read more.

Upregulation of miR-21 (microRNA-21) and downregulation of miR-34b/c have been found in breast cancer (BC). However, their regulation mechanism and function roles in BC have not been fully addressed. Here, we report that miR-21 levels were inversely correlated with miR-34b/c levels in BC. MiR-21 upregulation contributes to PTEN downregulation, which is beneficial for the activation of PI3K/AKT signaling. The activation of AKT phosphorylates FOXO3a, triggering relocalization of FOXO3a proteins from the nucleus to the cytoplasm. FOXO3a is a newly identified transcription factor responsible for miR-34b/c expression. Downregulation of nuclear FOXO3a decreased the expression levels of miR-34b and miR-34c in breast cancer cells, in which p53 was mutated. We also found upregulation of circulating miR-21 and downregulation of circulating miR-34b/c in BC patients’ serum. More importantly, we showed that systemic delivery of miR-34b/c or with anti-miR-21 significantly inhibited breast tumor growth in vivo. These results suggest that high circulating levels of miR-21 and low levels of miR-34b/c may provide potential biomarkers for BC diagnosis, and systemic delivery of miR-34b/c has potential as a therapeutic option for BC treatment. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells 2014)

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15 pages, 1276 KiB

Open AccessArticle

Differential Salt-Induced Dissociation of the p53 Protein Complexes with Circular and Linear Plasmid DNA Substrates Suggest Involvement of a Sliding Mechanism

by Peter Šebest¹, Marie Brázdová¹, Miroslav Fojta^1,2,* and Hana Pivoňková^1,*

¹ Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, Brno CZ-612 65, Czech Republic

² Central European Institute of Technology, Masaryk University, Kamenice 753/5, Brno CZ-625 00, Czech Republic

Int. J. Mol. Sci. 2015, 16(2), 3163-3177; https://doi.org/10.3390/ijms16023163 - 30 Jan 2015

Cited by 4 | Viewed by 6651

Abstract

A study of the effects of salt conditions on the association and dissociation of wild type p53 with different ~3 kbp long plasmid DNA substrates (supercoiled, relaxed circular and linear, containing or lacking a specific p53 binding site, p53CON) using immunoprecipitation at magnetic [...] Read more.

A study of the effects of salt conditions on the association and dissociation of wild type p53 with different ~3 kbp long plasmid DNA substrates (supercoiled, relaxed circular and linear, containing or lacking a specific p53 binding site, p53CON) using immunoprecipitation at magnetic beads is presented. Salt concentrations above 200 mM strongly affected association of the p53 protein to any plasmid DNA substrate. Strikingly different behavior was observed when dissociation of pre-formed p53-DNA complexes in increased salt concentrations was studied. While contribution from the p53CON to the stability of the p53-DNA complexes was detected between 100 and 170 mM KCl, p53 complexes with circular DNAs (but not linear) exhibited considerable resistance towards salt treatment for KCl concentrations as high as 2 M provided that the p53 basic C-terminal DNA binding site (CTDBS) was available for DNA binding. On the contrary, when the CTDBS was blocked by antibody used for immunoprecipitation, all p53-DNA complexes were completely dissociated from the p53 protein in KCl concentrations ≥200 mM under the same conditions. These observations suggest: (a) different ways for association and dissociation of the p53-DNA complexes in the presence of the CTDBS; and (b) a critical role for a sliding mechanism, mediated by the C-terminal domain, in the dissociation process. Full article

(This article belongs to the Section Biochemistry)

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10 pages, 1158 KiB

Open AccessArticle

CXCL13 Promotes the Effect of Bone Marrow Mesenchymal Stem Cells (MSCs) on Tendon-Bone Healing in Rats and in C3HIOT1/2 Cells

by Feng Tian^*, Xiang-Lu Ji^†, Wan-An Xiao^†, Bin Wang^† and Fei Wang^†

¹ Department of Orthopaedic Surgery, Shengjing Hospital of China Medical University, Shenyang 110024, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3178-3187; https://doi.org/10.3390/ijms16023178 - 30 Jan 2015

Cited by 24 | Viewed by 6478

Abstract

Objectives: Mesenchymal stem cells (MSCs) are potential effective therapy for tissue repair and bone regeneration. In present study, the effects of CXC chemokine ligand-13 (CXCL13) were evaluated on tendon-bone healing of rats. Methods: Tendon bone healing of the rat model was established and [...] Read more.

Objectives: Mesenchymal stem cells (MSCs) are potential effective therapy for tissue repair and bone regeneration. In present study, the effects of CXC chemokine ligand-13 (CXCL13) were evaluated on tendon-bone healing of rats. Methods: Tendon bone healing of the rat model was established and biomechanical testing was performed at 2, 4, 8 weeks after surgery. Murine mesenchymal cell line (C3HIOT1/2 cells) was cultured. The expression of miRNA-23a was detected by real-time PCR. The protein expression of ERK1/2, JNK and p38 was detected by western blotting. MiR-23a mimic and inhibitor were used to overexpress or silence the expression of miR-23a. Results: MSCs significantly elevated the levels of ultimate load to failure, stiffness and stress in specimens of rats, the effects of which were enhanced by CXCL13. The expression of miR-23a was down-regulated and the protein of ERK1/2 level was up-regulated by CXCL13 treatment in both in vivo and in vitro experiments. ERK1/2 expression was elevated by overexpression of miR-23a and reduced by miR-23a inhibitor. Conclusions: These findings revealed that CXCL13 promoted the tendon-bone healing in rats with MSCs treatment, and implied that the activation of ERK1/2 via miR-23a was involved in the process of MSCs treated bone regeneration. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 2561 KiB

Open AccessArticle

Multi-Walled Carbon Nanotubes Promote Cementoblast Differentiation and Mineralization through the TGF-β/Smad Signaling Pathway

by Lu Li, Zhimin Zhu, Weixiong Xiao and Lei Li^*

State Key Laboratory of Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China

Int. J. Mol. Sci. 2015, 16(2), 3188-3201; https://doi.org/10.3390/ijms16023188 - 2 Feb 2015

Cited by 25 | Viewed by 6257

Abstract

Excretion of cementum by cementoblasts on the root surface is a process indispensable for the formation of a functional periodontal ligament. This study investigated whether carboxyl group-functionalized multi-walled carbon nanotubes (MWCNT-COOH) could enhance differentiation and mineralization of mammalian cementoblasts (OCCM-30) and the possible [...] Read more.

Excretion of cementum by cementoblasts on the root surface is a process indispensable for the formation of a functional periodontal ligament. This study investigated whether carboxyl group-functionalized multi-walled carbon nanotubes (MWCNT-COOH) could enhance differentiation and mineralization of mammalian cementoblasts (OCCM-30) and the possible signaling pathway involved in this process. Cementoblasts were incubated with various doses of MWCNT-COOH suspension. Cell viability was detected, and a scanning electron microscopy (SEM) observed both the nanomaterials and the growth of cells cultured with the materials. Alizarin red staining was used to investigate the formation of calcium deposits. Real-time PCR and western blot were used to detect cementoblast differentiation and the underlying mechanisms through the expression of the osteogenic genes and the downstream effectors of the TGF-β/Smad signaling. The results showed that 5 µg/mL MWCNT-COOH had the most obvious effects on promoting differentiation without significant toxicity. Alp, Ocn, Bsp, Opn, Col1 and Runx2 gene expression was up-regulated. Smad2 and Smad3 mRNA was up-regulated, while Smad7 was first down-regulated on Day 3 and later up-regulated on Day 7. The elevated levels of phospho-Smad2/3 were also confirmed by western blot. In sum, the MWCNT-COOH promoted cementoblast differentiation and mineralization, at least partially, through interactions with the TGF-β/Smad pathway. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles 2014)

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11 pages, 2986 KiB

Open AccessArticle

Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents

by Chih-Hung Chuang^1,†, Ta-Chun Cheng^2,†, Yu-Ling Leu³, Kuo-Hsiang Chuang², Shey-Cherng Tzou⁴ and Chien-Shu Chen^5,*

¹ Institutes of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan

² Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, Taiwan

³ Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan

⁴ Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan

⁵ School of Pharmacy, China Medical University, Taichung 40402, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3202-3212; https://doi.org/10.3390/ijms16023202 - 2 Feb 2015

Cited by 36 | Viewed by 6875

Abstract

Akt acts as a pivotal regulator in the PI3K/Akt signaling pathway and represents a potential drug target for cancer therapy. To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal [...] Read more.

Akt acts as a pivotal regulator in the PI3K/Akt signaling pathway and represents a potential drug target for cancer therapy. To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal structure of human Akt kinase. From the virtual screening, 48 compounds were selected and subjected to the Akt kinase inhibition assay. Twenty-six of the test compounds showed more potent inhibitory effects on Akt kinase than the reference compound, H-89. These 26 compounds were further evaluated for their cytotoxicity against HCT-116 human colon cancer cells and HEK-293 normal human embryonic kidney cells. Twelve compounds were found to display more potent or comparable cytotoxic activity compared to compound H-89 against HCT-116 colon cancer cells. The best results were obtained with Compounds a46 and a48 having IC₅₀ values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC₅₀ for HEK-293/IC₅₀ for HCT-116) of 12.5 and 16.1, respectively. Through structure-based virtual screening and biological evaluations, we have successfully identified several new Akt inhibitors that displayed cytotoxic activity against HCT-116 human colon cancer cells. Especially, Compounds a46 and a48 may serve as useful lead compounds for further development of new anticancer agents. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 860 KiB

Open AccessArticle

Genetic Variants in the Apoptosis Gene BCL2L1 Improve Response to Interferon-Based Treatment of Hepatitis C Virus Genotype 3 Infection

by Louise Nygaard Clausen^1,2,3,*, Nina Weis^1,4, Steen Ladelund², Lone Madsen⁵, Suzanne Lunding⁶, Britta Tarp⁷, Peer Brehm Christensen⁸, Henrik Bygum Krarup⁹

, Axel Møller¹⁰, Jan Gerstoft¹¹, Mette Rye Clausen¹², Thomas Benfield^1,2,4 and The DANHEP group¹³

¹ Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre, Denmark

² Clinical Research Centre, Copenhagen University Hospital, 2650 Hvidovre, Denmark

³ Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre and Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, 2100 Copenhagen, Denmark

⁴ Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, 2100 Copenhagen, Denmark

⁵ Department of Gastroenterology, Køge Hospital, 4600 Køge, Denmark

⁶ Department of Infectious Diseases, Hillerød Hospital, 3400 Hillerød, Denmark

⁷ Diagnostic Center, Silkeborg Regional Hospital, 8600 Silkeborg, Denmark

⁸ Department of Infectious Diseases, Odense University Hospital, 5230 Odense, Denmark

⁹ Department of Gastroenterology and Department of Clinical Biochemistry, Section for Molecular Diagnostics, Aalborg University Hospital, 9100 Aalborg, Denmark

¹⁰ Department of Medicine, Kolding Regional Hospital, 6000 Kolding, Denmark

¹¹ Department of Infectious Diseases and Rheumatology, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark

¹² Department of Hepatology, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark

¹³ The DANHEP group (see Appendix 1)

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Int. J. Mol. Sci. 2015, 16(2), 3213-3225; https://doi.org/10.3390/ijms16023213 - 2 Feb 2015

Cited by 2 | Viewed by 6343

Abstract

Genetic variation upstream of the apoptosis pathway has been associated with outcome of hepatitis C virus (HCV) infection. We investigated genetic polymorphisms in the intrinsic apoptosis pathway to assess their influence on sustained virological response (SVR) to pegylated interferon-α and ribavirin (pegIFN/RBV) treatment [...] Read more.

Genetic variation upstream of the apoptosis pathway has been associated with outcome of hepatitis C virus (HCV) infection. We investigated genetic polymorphisms in the intrinsic apoptosis pathway to assess their influence on sustained virological response (SVR) to pegylated interferon-α and ribavirin (pegIFN/RBV) treatment of HCV genotypes 1 and 3 infections. We conducted a candidate gene association study in a prospective cohort of 201 chronic HCV-infected individuals undergoing treatment with pegIFN/RBV. Differences between groups were compared in logistic regression adjusted for age, HCV viral load and interleukin 28B genotypes. Four single nucleotide polymorphisms (SNPs) located in the B-cell lymphoma 2-like 1 (BCL2L1) gene were significantly associated with SVR. SVR rates were significantly higher for carriers of the beneficial rs1484994 CC genotypes. In multivariate logistic regression, the rs1484994 SNP combined CC + TC genotypes were associated with a 3.4 higher odds ratio (OR) in SVR for the HCV genotype 3 (p = 0.02). The effect estimate was similar for genotype 1, but the association did not reach statistical significance. In conclusion, anti-apoptotic SNPs in the BCL2L1 gene were predictive of SVR to pegIFN/RBV treatment in HCV genotypes 1 and 3 infected individuals. These SNPs may be used in prediction of SVR, but further studies are needed. Full article

(This article belongs to the Section Biochemistry)

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11 pages, 1519 KiB

Open AccessCommunication

MRS of Brain Metabolite Levels Demonstrates the Ability of Scavenging of Excess Brain Glutamate to Protect against Nerve Agent Induced Seizures

by Angela Ruban^1,*,†, Inbal E. Biton^2,†, Arik Markovich¹ and David Mirelman³

¹ Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel

² Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel

³ Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3226-3236; https://doi.org/10.3390/ijms16023226 - 2 Feb 2015

Cited by 13 | Viewed by 5792

Abstract

This study describes the use of in vivo magnetic resonance spectrocopy (MRS) to monitor brain glutamate and lactate levels in a paraoxon (PO) intoxication model. Our results show that the administration of recombinant glutamate-oxaloacetate transaminase (rGOT) in combination with oxaloacetate (OxAc) significantly reduces [...] Read more.

This study describes the use of in vivo magnetic resonance spectrocopy (MRS) to monitor brain glutamate and lactate levels in a paraoxon (PO) intoxication model. Our results show that the administration of recombinant glutamate-oxaloacetate transaminase (rGOT) in combination with oxaloacetate (OxAc) significantly reduces the brain-accumulated levels of glutamate. Previously we have shown that the treatment causes a rapid decrease of blood glutamate levels and creates a gradient between the brain and blood glutamate levels which leads to the efflux of excess brain glutamate into the blood stream thereby reducing its potential to cause neurological damage. The fact that this treatment significantly decreased the brain glutamate and lactate levels following PO intoxication suggests that it could become a new effective neuroprotective agent. Full article

(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)

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14 pages, 845 KiB

Open AccessArticle

Infiltrating Mast Cells Correlate with Angiogenesis in Bone Metastases from Gastric Cancer Patients

by Michele Ammendola^1,2, Ilaria Marech³, Giuseppe Sammarco¹, Valeria Zuccalà¹, Maria Luposella¹, Nicola Zizzo⁴

, Rosa Patruno⁴, Alberto Crovace^4,5, Eustachio Ruggieri², Alfredo Francesco Zito⁶, Cosmo Damiano Gadaleta³, Rosario Sacco¹ and Girolamo Ranieri^3,*

¹ Department of Medical and Surgical Sciences, Clinical Surgery Unit, University "Magna Graecia" Medical School, Viale Europa, Germaneto, Catanzaro 88100, Italy

² Surgery Unit, National Cancer Research Centre Istituto Tumori "Giovanni Paolo II", viale Orazio Flacco 65, Bari 70124, Italy

³ Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", viale Orazio Flacco 65, Bari 70124, Italy

⁴ Chair of Pathology, Veterinary Medical School, University "Aldo Moro" of Bari, Via Casamassima, Bari 70010, Italy

⁵ Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Via Casamassima, Bari 70010, Italy

⁶ Pathology Unit, ASL BA, Contrada Capo Scardicchio 92, Bari 70100, Italy

Int. J. Mol. Sci. 2015, 16(2), 3237-3250; https://doi.org/10.3390/ijms16023237 - 2 Feb 2015

Cited by 32 | Viewed by 7507

Abstract

While gastric cancer is a well established angiogenesis driven tumor, no data has been published regarding angiogenesis stimulated by mast cells (MCs) positive for tryptase in bone metastases from gastric cancer patients (BMGCP). It is well established that MCs play a role in [...] Read more.

While gastric cancer is a well established angiogenesis driven tumor, no data has been published regarding angiogenesis stimulated by mast cells (MCs) positive for tryptase in bone metastases from gastric cancer patients (BMGCP). It is well established that MCs play a role in immune responses and more recently it was demonstrated that MCs have been involved in tumor angiogenesis. We analyzed infiltrating MCs and neovascularization in BMGCP diagnosed by histology. A series of 15 stage T_3-4N_2-3M₁ (by AJCC for Gastric Cancer Staging 7th Edition) BMGCP from bone biopsies were selected. Tumour tissue samples were evaluated by mean of immunohistochemistry and image analysis methods in terms of MCs density positive to tryptase (MCDPT), MCs area positive to tryptase (MCAPT), microvascular density (MVD) and endothelial area (EA). A significant correlation between MCDPT, MCAPT, MVD and EA groups to each other was found by Pearson and t-test analysis (r ranged from 0.68 to 0.82; p-value ranged from 0.00 to 0.02). Our very preliminary data suggest that infiltrating MCs positive for tryptase may play a role in BMGCP angiogenesis, and could be further evaluated as a novel target of anti-angiogenic therapy. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 2251 KiB

Open AccessReview

Neighboring Gene Regulation by Antisense Long Non-Coding RNAs

by Victoria E. Villegas^1,2,*

and Peter G. Zaphiropoulos¹

¹ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 14183, Sweden

² Faculty of Natural Sciences and Mathematics & Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogotá 11001000, Colombia

Int. J. Mol. Sci. 2015, 16(2), 3251-3266; https://doi.org/10.3390/ijms16023251 - 3 Feb 2015

Cited by 254 | Viewed by 16571

Abstract

Antisense transcription, considered until recently as transcriptional noise, is a very common phenomenon in human and eukaryotic transcriptomes, operating in two ways based on whether the antisense RNA acts in cis or in trans. This process can generate long non-coding RNAs (lncRNAs), [...] Read more.

Antisense transcription, considered until recently as transcriptional noise, is a very common phenomenon in human and eukaryotic transcriptomes, operating in two ways based on whether the antisense RNA acts in cis or in trans. This process can generate long non-coding RNAs (lncRNAs), one of the most diverse classes of cellular transcripts, which have demonstrated multifunctional roles in fundamental biological processes, including embryonic pluripotency, differentiation and development. Antisense lncRNAs have been shown to control nearly every level of gene regulation—pretranscriptional, transcriptional and posttranscriptional—through DNA–RNA, RNA–RNA or protein–RNA interactions. This review is centered on functional studies of antisense lncRNA-mediated regulation of neighboring gene expression. Specifically, it addresses how these transcripts interact with other biological molecules, nucleic acids and proteins, to regulate gene expression through chromatin remodeling at the pretranscriptional level and modulation of transcriptional and post-transcriptional processes by altering the sense mRNA structure or the cellular compartmental distribution, either in the nucleus or the cytoplasm. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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16 pages, 5543 KiB

Open AccessArticle

mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer

by Feng Wei^1,†, Yandong Zhang^1,†, Li Geng², Ping Zhang¹, Guangyi Wang^1,* and Yan Liu^3,*

¹ Department of Hepatobiliary and Pancreas Surgery, the First Hospital, Jilin University, Changchun 130021, China

² Department of General Surgery, the Second Hospital of Jilin University, Changchun 130041, China

³ Genetic Engineering Laboratory of PLA, the Eleventh Institute of Academy of Military Medical Sciences of PLA, Changchun 130122, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3267-3282; https://doi.org/10.3390/ijms16023267 - 3 Feb 2015

Cited by 37 | Viewed by 8277

Abstract

The mammalian target of rapamycin (mTOR) is dysregulated in diverse cancers and contributes to tumor progression and drug resistance. The first generation of mTOR inhibitors have failed to show clinical efficiency in treating pancreatic cancers due in part to the feedback relief of [...] Read more.

The mammalian target of rapamycin (mTOR) is dysregulated in diverse cancers and contributes to tumor progression and drug resistance. The first generation of mTOR inhibitors have failed to show clinical efficiency in treating pancreatic cancers due in part to the feedback relief of the insulin-like growth factor-1 receptor (IGF-1R)-AKT signaling pathway. The second generation of mTOR inhibitors, such as AZD8055, could inhibit AKT activation upon mTOR complex 2 (mTORC2) inhibition. However, whether this generation of mTOR inhibitors can obtain satisfactory activities in pancreatic cancer therapy remains unclear. In this study, we found AZD8055 did not show great improvement compared with everolimus, AZD8055 induced a temporal inhibition of AKT kinase activities and AKT was then rephosphorylated. Additionally, we found that AZD8055-induced transient AKT inhibition increased the expression and activation of epidermal growth factor receptor (EGFR) by releasing its transcriptional factors Fork-head box O 1/3a (FoxO1/3a), which might contribute to cell resistance to AZD8055. The in vitro and in vivo experiments further indicated the combination of AZD8055 and erlotinib synergistically inhibited the mTORC1/C2 signaling pathway, EGFR/AKT feedback activation, and cell growth, as well as suppressed the progression of pancreatic cancer in a xenograft model. This study provides a rationale and strategy for overcoming AZD8055 resistance by a combined treatment with the EGFR inhibitor erlotinib in pancreatic cancer therapy. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 1206 KiB

Open AccessArticle

The Possible Physical Barrier and Coastal Dispersal Strategy for Japanese Grenadier Anchovy, Coilia nasus in the East China Sea and Yellow Sea: Evidence from AFLP Markers

by Zhi-Qiang Han¹, Gang Han², Zhi-Yong Wang³ and Tian-Xiang Gao^1,*

¹ Fishery College, Zhejiang Ocean University, Zhoushan 316022, China

² Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China

³ Fishery College, Jimei Universtiy, Xiamen 361021, China

Int. J. Mol. Sci. 2015, 16(2), 3283-3297; https://doi.org/10.3390/ijms16023283 - 3 Feb 2015

Cited by 10 | Viewed by 5736

Abstract

In order to ascertain the taxonomic status of the Ariake Sea population of Japanese grenadier anchovy, Coilia nasus, and assess the contemporary possible genetic barrier between the west and east coastal waters of the East China Sea, we used amplified fragment length [...] Read more.

In order to ascertain the taxonomic status of the Ariake Sea population of Japanese grenadier anchovy, Coilia nasus, and assess the contemporary possible genetic barrier between the west and east coastal waters of the East China Sea, we used amplified fragment length polymorphism (AFLP) markers to detect the genetic structure of C. nasus, in the East China Sea and Yellow Sea. Eighty-one individuals of C. nasus were collected from five locations and 12 individuals of Coilia mystus were sampled from the Yangtze River Estuary. A total of 371 loci were detected by five primer combinations, 310 of which were polymorphic (83.56%). Analysis of molecular variation (AMOVA) and pairwise fixation index (F_ST) revealed significant genetic differentiation among five samples, indicating limited gene flow among populations. The dendrogram for populations by neighbor-joining (NJ) cluster analysis provided evidence of a clear relationship between genetic and geographic patterns, supporting significant genetic differentiation between China coastal populations and Ariake Sea populations. Compared to the genetic divergence between C. nasus and C. mystus, the level of genetic differentiation between China and the Ariake Sea populations of C. nasus is obvious below the species level, indicating isolated populations of C. nasus in the Ariake Sea. Isolation by distance analysis revealed that direct ocean distance with deep-water at the continental slope and high salinity between west and east coastal waters of the East China Sea served as major physical barrier to C. nasus, supporting the coastal dispersal pattern in this estuarine species, and rejecting offshore dispersal strategy. Full article

(This article belongs to the Section Biochemistry)

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9 pages, 837 KiB

Open AccessArticle

Norcembranoidal Diterpenes from the Cultured-Type Octocoral Sinularia numerosa

by Wu-Fu Chen^1,†, Chen-Ting Yin^2,3,†, Ching-Hsiao Cheng¹, Mei-Chin Lu^2,3, Lee-Shing Fang⁴, Wei-Hsien Wang⁵, Zhi-Hong Wen⁵

, Jih-Jung Chen⁶

, Yang-Chang Wu^7,8,9,10,* and Ping-Jyun Sung^2,3,5,8,9,*

¹ Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

² Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, Taiwan

³ National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan

⁴ Department of Sport, Health and Leisure, Cheng Shiu University, Kaohsiung 833, Taiwan

⁵ Department of Marine Biotechnology and Resources and Division of Marine Biotechnology, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 804, Taiwan

⁶ Department of Pharmacy, Tajen University, Pingtung 907, Taiwan

⁷ School of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan

⁸ Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan

⁹ Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan

¹⁰ Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2015, 16(2), 3298-3306; https://doi.org/10.3390/ijms16023298 - 3 Feb 2015

Cited by 11 | Viewed by 5449

Abstract

A known norcembranoidal diterpene, 5-episinuleptolide (1), along with a new analogue, 4α-hydroxy-5-episinuleptolide (2), were isolated from a cultured-type soft coral Sinularia numerosa. The structures of 1 and 2 were elucidated on the basis of spectroscopic methods and by [...] Read more.

A known norcembranoidal diterpene, 5-episinuleptolide (1), along with a new analogue, 4α-hydroxy-5-episinuleptolide (2), were isolated from a cultured-type soft coral Sinularia numerosa. The structures of 1 and 2 were elucidated on the basis of spectroscopic methods and by comparison of the data with those of the related metabolites. Cytotoxicity of metabolites 1 and 2 against a panel of tumor cells is also described. Compound 2 exhibited moderate cytotoxicity toward CCRF-CEM cells with an IC₅₀ value 4.21 μg/mL. Preliminary SAR (structure activity relationship) information was obtained from these two compounds. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 703 KiB

Open AccessReview

Significant Roles of Regulatory T Cells and Myeloid Derived Suppressor Cells in Hepatitis B Virus Persistent Infection and Hepatitis B Virus-Related HCCs

by Yasuteru Kondo^* and Tooru Shimosegawa

Division of Gastroenterology, Tohoku University Graduate School of Medicine 1-1 Seiryo, Aoba, Sendai City, Miyagi 980-8574, Japan

Int. J. Mol. Sci. 2015, 16(2), 3307-3322; https://doi.org/10.3390/ijms16023307 - 3 Feb 2015

Cited by 47 | Viewed by 6738

Abstract

The adaptive immune system, including type1 helper T cells (Th1 cells), cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs), plays an important role in the control of hepatitis B virus (HBV). On the other hand, regulatory T cells (Tregs) and myeloid derived suppressor [...] Read more.

The adaptive immune system, including type1 helper T cells (Th1 cells), cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs), plays an important role in the control of hepatitis B virus (HBV). On the other hand, regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) suppress the immune reaction in HBV and hepatocellular carcinoma (HCC). Excessive activation of immune suppressive cells could contribute to the persistent infection of HBV and the progression of HCC. The frequency and/or function of Tregs could affect the natural course in chronic hepatitis B patients and the treatment response. In addition to the suppressive function of MDSCs, MDSCs could affect the induction and function of Tregs. Therefore, we should understand in detail the mechanism by which Tregs and MDSCs are induced to control HBV persistent infection and HBV-related HCC. Immune suppressive cells, including Tregs and MDSCs, contribute to the difficulty in inducing an effective immune response for HBV persistent infection and HBV-related HCC. In this review, we focus on the Tregs and MDSCs that could be potential targets for immune therapy of chronic hepatitis B and HBV-related HCC. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

12 pages, 1124 KiB

Open AccessArticle

Reduction of Oxidative Stress Attenuates Lipoapoptosis Exacerbated by Hypoxia in Human Hepatocytes

by Sang Youn Hwang¹, Su Jong Yu², Jeong-Hoon Lee², Hwi Young Kim³ and Yoon Jun Kim^2,*

¹ Department of Internal Medicine and Gastrointestinal Cancer Center, Dongnam Institute of Radiological & Medical Sciences, Busan KS012, Korea

² Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul KS013, Korea

³ Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul KS013, Korea

Int. J. Mol. Sci. 2015, 16(2), 3323-3334; https://doi.org/10.3390/ijms16023323 - 3 Feb 2015

Cited by 7 | Viewed by 6695

Abstract

Chronic intermittent hypoxia, a characteristic of obstructive sleep apnea (OSA), is associated with the progression of simple hepatic steatosis to necroinflammatory hepatitis. We determined whether inhibition of a hypoxia-induced signaling pathway could attenuate hypoxia-exacerbated lipoapoptosis in human hepatocytes. The human hepatocellular carcinoma cell [...] Read more.

Chronic intermittent hypoxia, a characteristic of obstructive sleep apnea (OSA), is associated with the progression of simple hepatic steatosis to necroinflammatory hepatitis. We determined whether inhibition of a hypoxia-induced signaling pathway could attenuate hypoxia-exacerbated lipoapoptosis in human hepatocytes. The human hepatocellular carcinoma cell line (HepG2) was used in this study. Palmitic acid (PA)-treated groups were used for two environmental conditions: Hypoxia (1% O₂) and normoxia (20% O₂). Following the treatment, the cell viability was determined by the 3,4-(5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay, and the mechanism of lipoapoptosis was evaluated by Western blotting. Hypoxia exacerbated the suppression of hepatocyte growth induced by palmitic acid via activation of mitochondrial apoptotic pathways as a result of endoplasmic reticulum (ER) and oxidative stresses. Ammonium pyrrolidine dithiocarbamate, a scavenger of reactive oxygen species, attenuated the hypoxia-exacerbated lipoapoptosis in hepatocytes, whereas glycerol, which reduces ER stress, did not. This may have been because inhibition of oxidative stress decreases the expression of pro-apoptotic proteins, such as caspase 9 and cytochrome c. These results suggested that modulation of apoptotic signaling pathways activated by oxidative stress can aid in identifying novel therapeutic strategies for the treatment of nonalcoholic steatohepatitis (NASH) with OSA. Further in vivo studies are necessary to understand the pathophysiologic mechanism of NASH with OSA and to prove the therapeutic effect of the modulation of the signaling pathways. Full article

(This article belongs to the Special Issue Antioxidant 2.0——Redox Modulation by Food and Drugs)

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15 pages, 4613 KiB

Open AccessArticle

Ecdysone Receptor (EcR) Is Involved in the Transcription of Cell Cycle Genes in the Silkworm

by Wenliang Qian, Lixia Kang, Tianlei Zhang, Meng Meng, Yonghu Wang, Zhiqing Li, Qingyou Xia^*

and Daojun Cheng^*

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, China

Int. J. Mol. Sci. 2015, 16(2), 3335-3349; https://doi.org/10.3390/ijms16023335 - 3 Feb 2015

Cited by 3 | Viewed by 7499

Abstract

EcR (ecdysone receptor)-mediated ecdysone signaling pathway contributes to regulate the transcription of genes involved in various processes during insect development. In this work, we detected the expression of EcR gene in silkworm ovary-derived BmN4 cells and found that EcR RNAi result in an [...] Read more.

EcR (ecdysone receptor)-mediated ecdysone signaling pathway contributes to regulate the transcription of genes involved in various processes during insect development. In this work, we detected the expression of EcR gene in silkworm ovary-derived BmN4 cells and found that EcR RNAi result in an alteration of cell shape, indicating that EcR may orchestrate cell cycle progression. EcR RNAi and EcR overexpression analysis revealed that in the cultured BmN4 cells, EcR respectively promoted and suppressed the transcription of E2F-1 and CycE, two genes controlling cell cycle progression. Further examination demonstrated that ecdysone application in BmN4 cells not only changed the transcription of these two cell cycle genes like that under EcR overexpression, but also induced cell cycle arrest at G2/M phase. In vivo analysis confirmed that E2F-1 expression was elevated in silk gland of silkworm larvae after ecdysone application, which is same as its response to ecdysone in BmN4 cells. However, ecdysone also promotes CycE transcription in silk gland, and this is converse with the observation in BmN4 cells. These results provide new insights into understanding the roles of EcR-mediated ecdysone signaling in the regulation of cell cycle. Full article

(This article belongs to the Section Biochemistry)

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27 pages, 1969 KiB

Open AccessReview

Dietary Polyphenols in Prevention and Treatment of Prostate Cancer

by Rahul K. Lall^1,2, Deeba N. Syed², Vaqar M. Adhami², Mohammad Imran Khan² and Hasan Mukhtar^2,*

¹ Department of Food Science, University of Wisconsin, Madison, WI 53706, USA

² Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA

Int. J. Mol. Sci. 2015, 16(2), 3350-3376; https://doi.org/10.3390/ijms16023350 - 3 Feb 2015

Cited by 175 | Viewed by 19948

Abstract

Prostate cancer is the most prevalent disease affecting males in many Western countries, with an estimated 29,480 deaths in 2014 in the US alone. Incidence rates for prostate cancer deaths have been decreasing since the early 1990s in men of all races/ethnicities, though [...] Read more.

Prostate cancer is the most prevalent disease affecting males in many Western countries, with an estimated 29,480 deaths in 2014 in the US alone. Incidence rates for prostate cancer deaths have been decreasing since the early 1990s in men of all races/ethnicities, though they remain about 60% higher in African Americans than in any other group. The relationship between dietary polyphenols and the prevention of prostate cancer has been examined previously. Although results are sometimes inconsistent and variable, there is a general agreement that polyphenols hold great promise for the future management of prostate cancer. Various dietary components, including polyphenols, have been shown to possess anti-cancer properties. Generally considered as non-toxic, dietary polyphenols act as key modulators of signaling pathways and are therefore considered ideal chemopreventive agents. Besides possessing various anti-tumor properties, dietary polyphenols also contribute to epigenetic changes associated with the fate of cancer cells and have emerged as potential drugs for therapeutic intervention. Polyphenols have also been shown to affect post-translational modifications and microRNA expressions. This article provides a systematic review of the health benefits of selected dietary polyphenols in prostate cancer, especially focusing on the subclasses of polyphenols, which have a great effect on disease prevention and treatment. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals in Functional Foods for Cancer Prevention)

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14 pages, 755 KiB

Open AccessArticle

Predicted Trans-Acting siRNAs in the Human Brain

by Xiaoshuang Liu¹, Guangxin Zhang¹, Changqing Zhang^2,* and Jin Wang^1,*

¹ The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China

² College of Horticulture, Jinling Institute of Technology, Nanjing 210038, China

Int. J. Mol. Sci. 2015, 16(2), 3377-3390; https://doi.org/10.3390/ijms16023377 - 3 Feb 2015

Cited by 4 | Viewed by 5997

Abstract

Endogenous small non-coding RNAs play pivotal roles in regulating gene expression in eukaryotes. Many studies have investigated the function and molecular mechanism of microRNAs in the development and disease of various organisms via mRNA repression of protein-coding genes. Recent findings indicate microRNAs might [...] Read more.

Endogenous small non-coding RNAs play pivotal roles in regulating gene expression in eukaryotes. Many studies have investigated the function and molecular mechanism of microRNAs in the development and disease of various organisms via mRNA repression of protein-coding genes. Recent findings indicate microRNAs might trigger the generation of trans-acting small interfering RNAs (ta-siRNAs). The interaction among different types of small RNA molecules reveals an even more complicated and elaborate pattern of RNA regulation during gene expression than previously thought. We developed a method for mining ta-siRNA sequences and evaluated the performance of our novel method using data from Arabidopsis thaliana. Additionally, using small RNA and degradome data for the human brain, we identified 155 small RNAs that satisfied ta-siRNA characteristics. The DRAXIN and ATCAY genes, which are preferentially expressed in the human brain, were predicted to be the targets of 12 potential ta-siRNAs. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 1480 KiB

Open AccessArticle

Expression and Significance of CD44, CD47 and c-met in Ovarian Clear Cell Carcinoma

by Huimin Wang, Mingzi Tan, Song Zhang, Xiao Li, Jian Gao, Danye Zhang, Yingying Hao, Song Gao, Juanjuan Liu and Bei Lin^*

Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, No. 36 Sanhao Street, Heping District, Shenyang 110004, China

Int. J. Mol. Sci. 2015, 16(2), 3391-3404; https://doi.org/10.3390/ijms16023391 - 4 Feb 2015

Cited by 69 | Viewed by 8007

Abstract

Aims: The aim of the present study is to investigate the differential expression of CD44, CD47 and c-met in ovarian clear cell carcinoma (OCCC), the correlation in their expression and their relationship with the biological behavior of OCCC. Methods: We used immunohistochemistry to [...] Read more.

Aims: The aim of the present study is to investigate the differential expression of CD44, CD47 and c-met in ovarian clear cell carcinoma (OCCC), the correlation in their expression and their relationship with the biological behavior of OCCC. Methods: We used immunohistochemistry to examine the expression of CD44, CD47 and c-met in OCCC (86 cases) and investigated the effects of the expression and interaction of these molecules on the development of OCCC. Results: CD44, CD47 and c-met expression was significantly high in OCCC. Expression of CD44 and CD47 correlated with patient surgical stage, chemotherapy resistance and prognosis (all p < 0.05), and expression of c-met correlated with chemotherapy resistance and prognosis (all p < 0.05), but did not correlate with lymph node metastasis (all p > 0.05). The surgical stage, CD44, CD47 and c-met expression were independent risk factors for OCCC prognosis (all p < 0.05). Patients with low levels of CD44, CD47 and c-met showed better survival than those with high levels (all p < 0.05). There was a positive correlation between CD44 (or CD47) and c-met, as well as between CD44 and CD47 (the Spearman correlation coefficient r_swas 0.783, 0.776 and 0.835, respectively, all p < 0.01). Additionally, pairwise correlation analysis of these three markers shows that the high expression of CD44/CD47, CD44/c-met and CD47/c-met were correlated with patient surgical stage, chemotherapy resistance and prognosis (all p < 0.05), but did not correlate with lymph node metastasis (all p > 0.05). Conclusions: Expression of CD44, CD47 and c-met was upregulated in OCCC and pairwise correlation. CD44, CD47 and c-met may have synergistic effects on the development of OCCC and are prognostic factors for ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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14 pages, 947 KiB

Open AccessArticle

Chemical Modeling of Acid-Base Properties of Soluble Biopolymers Derived from Municipal Waste Treatment Materials

by Silvia Tabasso¹

, Silvia Berto^1,*, Roberta Rosato¹, Janeth Alicia Tafur Marinos¹, Marco Ginepro¹, Vincenzo Zelano¹, Pier Giuseppe Daniele¹ and Enzo Montoneri²

¹ Department of Chemistry, University of Turin, Via Pietro Giuria 7, I-10125 Torino, Italy

² Biowaste Processing, Via XXIV Maggio 25, 37126 Verona, Italy

Int. J. Mol. Sci. 2015, 16(2), 3405-3418; https://doi.org/10.3390/ijms16023405 - 4 Feb 2015

Cited by 7 | Viewed by 6843

Abstract

This work reports a study of the proton-binding capacity of biopolymers obtained from different materials supplied by a municipal biowaste treatment plant located in Northern Italy. One material was the anaerobic fermentation digestate of the urban wastes organic humid fraction. The others were [...] Read more.

This work reports a study of the proton-binding capacity of biopolymers obtained from different materials supplied by a municipal biowaste treatment plant located in Northern Italy. One material was the anaerobic fermentation digestate of the urban wastes organic humid fraction. The others were the compost of home and public gardening residues and the compost of the mix of the above residues, digestate and sewage sludge. These materials were hydrolyzed under alkaline conditions to yield the biopolymers by saponification. The biopolymers were characterized by ¹³C NMR spectroscopy, elemental analysis and potentiometric titration. The titration data were elaborated to attain chemical models for interpretation of the proton-binding capacity of the biopolymers obtaining the acidic sites concentrations and their protonation constants. The results obtained with the models and by NMR spectroscopy were elaborated together in order to better characterize the nature of the macromolecules. The chemical nature of the biopolymers was found dependent upon the nature of the sourcing materials. Full article

(This article belongs to the Special Issue Green Chemistry and the Biorefinery)

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15 pages, 5059 KiB

Open AccessArticle

Three-Dimensional Collagen Type I Matrix Up-Regulates Nuclear Isoforms of the Microtubule Associated Protein Tau Implicated in Resistance to Paclitaxel Therapy in Ovarian Carcinoma

by Hilal Gurler¹, Yi Yu¹, Jacqueline Choi², Andre A. Kajdacsy-Balla² and Maria V. Barbolina^1,*

¹ Department of Biopharmaceutical Sciences, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA

² Department of Pathology, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA

Int. J. Mol. Sci. 2015, 16(2), 3419-3433; https://doi.org/10.3390/ijms16023419 - 4 Feb 2015

Cited by 30 | Viewed by 6057

Abstract

Epithelial ovarian carcinoma is the deadliest gynecologic malignancy. One reason underlying treatment failure is resistance to paclitaxel. Expression of the microtubule associated protein tau has recently been proposed as a predictor of response to paclitaxel in ovarian carcinoma patients. Expression of tau was [...] Read more.

Epithelial ovarian carcinoma is the deadliest gynecologic malignancy. One reason underlying treatment failure is resistance to paclitaxel. Expression of the microtubule associated protein tau has recently been proposed as a predictor of response to paclitaxel in ovarian carcinoma patients. Expression of tau was probed using immunohistochemistry in 312 specimens of primary, and 40 specimens of metastatic, ovarian carcinoma. Serous epithelial ovarian carcinoma cell line models were used to determine the expression of tau by Western blot and immunofluorescence staining. Subcellular fractionation and Western blot were employed to examine nuclear and cytoplasmic localization of tau. Gene silencing and clonogenic assays were used to evaluate paclitaxel response. Tau was expressed in 44% of all tested cases. Among the primary serous epithelial ovarian carcinoma cases, 46% were tau-positive. Among the metastatic serous epithelial ovarian carcinomas, 63% were tau-positive. Cell culture experiments demonstrated that tau was expressed in multiple isoforms. Three-dimensional collagen I matrix culture conditions resulted in up-regulation of tau protein. Silencing of tau with specific siRNAs in a combination with three-dimensional culture conditions led to a significant decrease of the clonogenic ability of cells treated with paclitaxel. The data suggest that reduction of tau expression may sensitize ovarian carcinoma to the paclitaxel treatment. Full article

(This article belongs to the Section Biochemistry)

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7 pages, 622 KiB

Open AccessCommentary

Current Status of Photodynamic Therapy in Digestive Tract Carcinoma in Japan

by Atsushi Nanashima^*,† and Takeshi Nagayasu^†

¹ Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1, Sakamoto, Nagasaki 852-8501, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3434-3440; https://doi.org/10.3390/ijms16023434 - 4 Feb 2015

Cited by 15 | Viewed by 5588

Abstract

Photodynamic therapy (PDT) is an effective local treatment modality as a cancer-specific laser ablation in malignancy of some organs including digestive tracts or bile duct. In Japan, PDT has been applied at the early period after the first clinical induction in 1980’s. Although [...] Read more.

Photodynamic therapy (PDT) is an effective local treatment modality as a cancer-specific laser ablation in malignancy of some organs including digestive tracts or bile duct. In Japan, PDT has been applied at the early period after the first clinical induction in 1980’s. Although the useful efficacy was clarified, PDT has not been fully applied because of the phototoxicity of the porfimer sodium. The next generated talaporfin-sodium was used for PDT, in which phototoxicity was reduced and, however, the clinical efficacy for digestive tract malignancy has not yet been clarified. By proceeding the experimental and clinical trials, it is necessary to clarify the evidence of efficacy as a local powerful treatment with the conventional surgery, brachiotherapy and chemotherapy in the future step. Full article

(This article belongs to the Special Issue Advances in Photodynamic Therapy)

11 pages, 2934 KiB

Open AccessArticle

Synthesis of a Temperature-Sensitive Matrine-Imprinted Polymer and Its Potential Application for the Selective Extraction of Matrine from Radix Sophorae Tonkinensis

by Minjie Jiang¹, Lisheng Wang^1,*, Xu Liu¹, Hua Yang¹, Fan Ren¹, Lizhen Gan² and Weizhe Jiang^2,*

¹ School of Chemistry and Chemical Engineering, Guangxi University, 100 Daxue Road, Nanning 530004, China

² School of Pharmaceutical, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, China

Int. J. Mol. Sci. 2015, 16(2), 3441-3451; https://doi.org/10.3390/ijms16023441 - 4 Feb 2015

Cited by 8 | Viewed by 6383

Abstract

A temperature-sensitive matrine-imprinted polymer was prepared in chloroform by free-radical cross-linking copolymerization of methacrylic acid at 60 °C in the presence of ethylene glycol dimethacrylate as the cross-linker, N-isopropyl acrylamide as the temperature-responsive monomer and matrine as the template molecule. Binding experiments [...] Read more.

A temperature-sensitive matrine-imprinted polymer was prepared in chloroform by free-radical cross-linking copolymerization of methacrylic acid at 60 °C in the presence of ethylene glycol dimethacrylate as the cross-linker, N-isopropyl acrylamide as the temperature-responsive monomer and matrine as the template molecule. Binding experiments and Scatchard analyses revealed that two classes of binding sites were formed on molecular imprinted polymer (MIP) at 50 °C. Additionally, the thermoresponsive MIP was tested for its application as a sorbent material for the selective separation of matrine from Chinese medicinal plant radix Sophorae tonkinensis. It was shown that the thermoresponsive MIP displayed different efficiency in clean-up and enrichments using the SPE protocol at different temperatures. Full article

(This article belongs to the Section Molecular Recognition)

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22 pages, 2102 KiB

Open AccessReview

Starting to Gel: How Arabidopsis Seed Coat Epidermal Cells Produce Specialized Secondary Cell Walls

by Cătălin Voiniciuc^1,2, Bo Yang², Maximilian Heinrich-Wilhelm Schmidt^1,2, Markus Günl¹ and Björn Usadel^1,2,*

¹ Institute for Bio- and Geosciences (IBG-2: Plant Sciences), Forschungszentrum Jülich, 52425 Jülich, Germany

² Institute for Botany and Molecular Genetics (IBMG), RWTH Aachen University, 52056 Aachen, Germany

Int. J. Mol. Sci. 2015, 16(2), 3452-3473; https://doi.org/10.3390/ijms16023452 - 4 Feb 2015

Cited by 96 | Viewed by 13410

Abstract

For more than a decade, the Arabidopsis seed coat epidermis (SCE) has been used as a model system to study the synthesis, secretion and modification of cell wall polysaccharides, particularly pectin. Our detailed re-evaluation of available biochemical data highlights that Arabidopsis seed mucilage [...] Read more.

For more than a decade, the Arabidopsis seed coat epidermis (SCE) has been used as a model system to study the synthesis, secretion and modification of cell wall polysaccharides, particularly pectin. Our detailed re-evaluation of available biochemical data highlights that Arabidopsis seed mucilage is more than just pectin. Typical secondary wall polymers such as xylans and heteromannans are also present in mucilage. Despite their low abundance, these components appear to play essential roles in controlling mucilage properties, and should be further investigated. We also provide a comprehensive community resource by re-assessing the mucilage phenotypes of almost 20 mutants using the same conditions. We conduct an in-depth functional evaluation of all the SCE genes described in the literature and propose a revised model for mucilage production. Further investigation of SCE cells will improve our understanding of plant cell walls. Full article

(This article belongs to the Special Issue Plant Molecular Biology)

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19 pages, 963 KiB

Open AccessArticle

Comprehensive DNA Adduct Analysis Reveals Pulmonary Inflammatory Response Contributes to Genotoxic Action of Magnetite Nanoparticles

by Kousuke Ishino¹, Tatsuya Kato¹, Mamoru Kato², Tatsuhiro Shibata², Masatoshi Watanabe³, Keiji Wakabayashi⁴, Hitoshi Nakagama¹ and Yukari Totsuka^1,*

¹ Division of Carcinogenesis and Prevention, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan

² Division of Cancer Genomics, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan

³ Division of Materials Science and Engineering, Graduate School of Engineering, Yokohama National University, Hodogaya-ku, Yokohama 240-8501, Japan

⁴ Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka, 52-1, Yada, Shizuoka 422-8526, Japan

Int. J. Mol. Sci. 2015, 16(2), 3474-3492; https://doi.org/10.3390/ijms16023474 - 4 Feb 2015

Cited by 43 | Viewed by 6806

Abstract

Nanosized-magnetite (MGT) is widely utilized in medicinal and industrial fields; however, its toxicological properties are not well documented. In our previous report, MGT showed genotoxicity in both in vitro and in vivo assay systems, and it was suggested that inflammatory responses exist behind [...] Read more.

Nanosized-magnetite (MGT) is widely utilized in medicinal and industrial fields; however, its toxicological properties are not well documented. In our previous report, MGT showed genotoxicity in both in vitro and in vivo assay systems, and it was suggested that inflammatory responses exist behind the genotoxicity. To further clarify mechanisms underlying the genotoxicity, a comprehensive DNA adduct (DNA adductome) analysis was conducted using DNA samples derived from the lungs of mice exposed to MGT. In total, 30 and 42 types of DNA adducts were detected in the vehicle control and MGT-treated groups, respectively. Principal component analysis (PCA) against a subset of DNA adducts was applied and several adducts, which are deduced to be formed by inflammation or oxidative stress, as the case of etheno-deoxycytidine (εdC), revealed higher contributions to MGT exposure. By quantitative-LC-MS/MS analysis, εdC levels were significantly higher in MGT-treated mice than those of the vehicle control. Taken together with our previous data, it is suggested that inflammatory responses might be involved in the genotoxicity induced by MGT in the lungs of mice. Full article

(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)

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19 pages, 2266 KiB

Open AccessArticle

Transcriptome Profiling and Identification of Transcription Factors in Ramie (Boehmeria nivea L. Gaud) in Response to PEG Treatment, Using Illumina Paired-End Sequencing Technology

by Xia An^†

, Jie Chen^†, Jingyu Zhang, Yiwen Liao, Lunjin Dai, Bo Wang^*, Lijun Liu and Dingxiang Peng^*

¹ Key Laboratory of Crop Ecophysiology and Farming Systems in the Middle Reaches of the Yangtze River, Ministry of Agriculture, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3493-3511; https://doi.org/10.3390/ijms16023493 - 4 Feb 2015

Cited by 42 | Viewed by 7760

Abstract

Ramie (Boehmeria nivea L. Gaud), commonly known as China grass, is a perennial bast fiber plant of the Urticaceae. In China, ramie farming, industry, and trade provide income for about five million people. Drought stress severely affects ramie stem growth and causes [...] Read more.

Ramie (Boehmeria nivea L. Gaud), commonly known as China grass, is a perennial bast fiber plant of the Urticaceae. In China, ramie farming, industry, and trade provide income for about five million people. Drought stress severely affects ramie stem growth and causes a dramatic decrease in ramie fiber production. There is a need to enhance ramie’s tolerance to drought stress. However, the drought stress regulatory mechanism in ramie remains unknown. Water stress imposed by polyethylene glycol (PEG) is a common and convenient method to evaluate plant drought tolerance. In this study, transcriptome analysis of cDNA collections from ramie subjected to PEG treatment was conducted using Illumina paired-end sequencing, which generated 170 million raw sequence reads. Between leaves and roots subjected to 24 (L2 and R2) and 72 (L3 and R3) h of PEG treatment, 16,798 genes were differentially expressed (9281 in leaves and 8627 in roots). Among these, 25 transcription factors (TFs) from the AP2 (3), MYB (6), NAC (9), zinc finger (5), and bZIP (2) families were considered to be associated with drought stress. The identified TFs could be used to further investigate drought adaptation in ramie. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 3911 KiB

Open AccessArticle

Phytochemical Composition and Anti-Inflammatory Activity of Extracts from the Whole-Meal Flour of Italian Durum Wheat Cultivars

by Barbara Laddomada^1,*, Miriana Durante¹

, Fiorenza Minervini², Antonella Garbetta², Angela Cardinali²

, Isabella D'Antuono²

, Sofia Caretto¹, Antonio Blanco³ and Giovanni Mita¹

¹ Institute of Sciences of Food Production, CNR, 73100 Lecce, Italy

² Institute of Sciences of Food Production, CNR, 70125 Bari, Italy

³ Department of Soil, Plant and Food Sciences, Section of Genetic and Plant Breeding, University of Bari Aldo Moro, 70124 Bari, Italy

Int. J. Mol. Sci. 2015, 16(2), 3512-3527; https://doi.org/10.3390/ijms16023512 - 4 Feb 2015

Cited by 37 | Viewed by 6544

Abstract

In this study, the quali-quantitative composition of hydrophilic (phenolic acids) and lipophilic (isoprenoids) extracts from whole-meal flour of five elite Italian durum wheat cultivars was determined. Significant differences in the content of bioactive compounds were observed among the wheat extracts, in particular concerning [...] Read more.

In this study, the quali-quantitative composition of hydrophilic (phenolic acids) and lipophilic (isoprenoids) extracts from whole-meal flour of five elite Italian durum wheat cultivars was determined. Significant differences in the content of bioactive compounds were observed among the wheat extracts, in particular concerning the content of bound phenolic acids, lutein and β-tocotrienols. The cultivars Duilio and Svevo showed the highest amount of phenolic acids and isoprenoids, respectively. Extracts were evaluated for their anti-inflammatory activity on HT-29 human colon cells by measuring the levels of interleukin 8 (IL-8) and transforming growth factor β1 (TGF-β1). Durum wheat extracts significantly inhibited the secretion of the pro-inflammatory IL-8 mediator at 66 µg/mL of phenolic acids and at 0.2 µg/mL of isoprenoids. Conversely, the secretion of the anti-inflammatory mediator TGF-β1 was not modified by neither hydrophilic nor lipophilic extracts. These results provide further insight into the potential of durum wheat on human health suggesting the significance of varieties with elevated contents of bioactive components. Full article

(This article belongs to the Section Biochemistry)

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9 pages, 1984 KiB

Open AccessArticle

Oxidative Stress-Mediated Apoptosis Induced by Ethanolic Mango Seed Extract in Cultured Estrogen Receptor Positive Breast Cancer MCF-7 Cells

by Al-Shwyeh Hussah Abdullah¹, Abdulkarim Sabo Mohammed^1,*, Abdullah Rasedee^2,3 and Mohamed Elwathig Saeed Mirghani⁴

¹ Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

² Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

³ Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

⁴ Department of Biotechnology Engineering Faculty of Engineering, International Islamic, University Malaysia (IIUM), 50728 Kuala Lumpur, Malaysia

Int. J. Mol. Sci. 2015, 16(2), 3528-3536; https://doi.org/10.3390/ijms16023528 - 5 Feb 2015

Cited by 37 | Viewed by 6900

Abstract

Breast cancer has become a global health issue requiring huge expenditures for care and treatment of patients. There is a need to discover newer cost-effective alternatives for current therapeutic regimes. Mango kernel is a waste product with potential as a source of anti-cancer [...] Read more.

Breast cancer has become a global health issue requiring huge expenditures for care and treatment of patients. There is a need to discover newer cost-effective alternatives for current therapeutic regimes. Mango kernel is a waste product with potential as a source of anti-cancer phytochemicals, especially since it is non-toxic towards normal breast cell lines at concentrations for which it induces cell death in breast cancer cells. In this study, the anti-cancer effect of mango kernel extract was determined on estrogen receptor-positive human breast carcinoma (MCF-7) cells. The MCF-7 cells were cultured and treated with 5, 10 and 50 μg/mL of mango kernel extract for 12 and 24 h. In response to treatment, there were time- and dose-dependent increases in oxidative stress markers and pro-apoptotic factors; Bcl-2-like protein 4 (BAX), p53, cytochrome c and caspases (7, 8 and 9) in the MCF-7 cells treated with the extract. At the same time, there were decreases in pro-survival markers (Bcl-2 and glutathione) as the result of the treatments. The changes induced in the MCF-7 cells by mango kernel extract treatment suggest that the extract can induce cancer cell apoptosis, likely via the activation of oxidative stress. These findings need to be evaluated further to determine whether mango kernel extract can be developed as an anti-breast cancer agent. Full article

(This article belongs to the Section Biochemistry)

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27 pages, 1882 KiB

Open AccessReview

Proteomic Challenges: Sample Preparation Techniques for Microgram-Quantity Protein Analysis from Biological Samples

by Peter Feist and Amanda B. Hummon^*

Department of Chemistry and Biochemistry, Integrated Biomedical Sciences Program, and the Harper Cancer Research Institute, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA

Int. J. Mol. Sci. 2015, 16(2), 3537-3563; https://doi.org/10.3390/ijms16023537 - 5 Feb 2015

Cited by 228 | Viewed by 24012

Abstract

Proteins regulate many cellular functions and analyzing the presence and abundance of proteins in biological samples are central focuses in proteomics. The discovery and validation of biomarkers, pathways, and drug targets for various diseases can be accomplished using mass spectrometry-based proteomics. However, with [...] Read more.

Proteins regulate many cellular functions and analyzing the presence and abundance of proteins in biological samples are central focuses in proteomics. The discovery and validation of biomarkers, pathways, and drug targets for various diseases can be accomplished using mass spectrometry-based proteomics. However, with mass-limited samples like tumor biopsies, it can be challenging to obtain sufficient amounts of proteins to generate high-quality mass spectrometric data. Techniques developed for macroscale quantities recover sufficient amounts of protein from milligram quantities of starting material, but sample losses become crippling with these techniques when only microgram amounts of material are available. To combat this challenge, proteomicists have developed micro-scale techniques that are compatible with decreased sample size (100 μg or lower) and still enable excellent proteome coverage. Extraction, contaminant removal, protein quantitation, and sample handling techniques for the microgram protein range are reviewed here, with an emphasis on liquid chromatography and bottom-up mass spectrometry-compatible techniques. Also, a range of biological specimens, including mammalian tissues and model cell culture systems, are discussed. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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15 pages, 1687 KiB

Open AccessArticle

Characterisation of Two Oxidosqualene Cyclases Responsible for Triterpenoid Biosynthesis in Ilex asprella

by Xiasheng Zheng^1,2, Xiuxiu Luo¹, Guobing Ye¹, Ye Chen¹, Xiaoyu Ji¹, Lingling Wen¹, Yaping Xu¹, Hui Xu^1,*, Ruoting Zhan¹ and Weiwen Chen^1,*

¹ Research Center of Chinese Herbal Resource Science and Engineering, Key Laboratory of Chinese Medicinal Resource from Lingnan, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

² The Key Laboratory of Technology of Breaking Cell Wall and Application in Chinese Medicine Decoction Pieces, Zhongshan Zhongzhi Pharmaceutical Group, Zhongshan 528437, China

Int. J. Mol. Sci. 2015, 16(2), 3564-3578; https://doi.org/10.3390/ijms16023564 - 5 Feb 2015

Cited by 32 | Viewed by 9936

Abstract

Ilex asprella, a plant widely used as a folk herbal drug in southern China, produces and stores a large amount of triterpenoid saponins, most of which are of the α-amyrin type. In this study, two oxidosqualene cyclase (OSC) cDNAs, IaAS1 and IaAS2 [...] Read more.

Ilex asprella, a plant widely used as a folk herbal drug in southern China, produces and stores a large amount of triterpenoid saponins, most of which are of the α-amyrin type. In this study, two oxidosqualene cyclase (OSC) cDNAs, IaAS1 and IaAS2, were cloned from the I. asprella root. Functional characterisation was performed by heterologous expression in the yeast Saccharomyces cerevisiae. Analysis of the resulting products by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) showed that both genes encode a mixed amyrin synthase, producing α-amyrin and β-amyrin at different ratios. IaAS1, which mainly produces α-amyrin, is the second triterpene synthase so far identified in which the level of α-amyrin produced is ≥80% of total amyrin production. By contrast, IaAS2 mainly synthesises β-amyrin, with a yield of 95%. Gene expression patterns of these two amyrin synthases in roots and leaves of I. asprella were found to be consistent with the content patterns of total saponins. Finally, phylogenetic analysis and multiple sequence alignment of the two amyrin synthases against several known OSCs from other plants were conducted to further elucidate their evolutionary relationship. Full article

(This article belongs to the Special Issue Metabolomics in the Plant Sciences)

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20 pages, 4344 KiB

Open AccessArticle

Analysis of Dermal Papilla Cell Interactome Using STRING Database to Profile the ex Vivo Hair Growth Inhibition Effect of a Vinca Alkaloid Drug, Colchicine

by Ching-Wu Hsia¹, Ming-Yi Ho², Hao-Ai Shui³, Chong-Bin Tsai^1,4,* and Min-Jen Tseng^1,*

¹ Institute of Molecular Biology and Department of Life Science, National Chung Cheng University, Chia-yi 621, Taiwan

² Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan

³ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan

⁴ Department of Ophthalmology, Chia-yi Christian Hospital, Chia-yi 600, Taiwan

Int. J. Mol. Sci. 2015, 16(2), 3579-3598; https://doi.org/10.3390/ijms16023579 - 5 Feb 2015

Cited by 27 | Viewed by 8560

Abstract

Dermal papillae (DPs) control the formation of hair shafts. In clinical settings, colchicine (CLC) induces patients’ hair shedding. Compared to the control, the ex vivo hair fiber elongation of organ cultured vibrissa hair follicles (HFs) declined significantly after seven days of CLC treatment. [...] Read more.

Dermal papillae (DPs) control the formation of hair shafts. In clinical settings, colchicine (CLC) induces patients’ hair shedding. Compared to the control, the ex vivo hair fiber elongation of organ cultured vibrissa hair follicles (HFs) declined significantly after seven days of CLC treatment. The cultured DP cells (DPCs) were used as the experimental model to study the influence of CLC on the protein dynamics of DPs. CLC could alter the morphology and down-regulate the expression of alkaline phosphatase (ALP), the marker of DPC activity, and induce IκBα phosphorylation of DPCs. The proteomic results showed that CLC modulated the expression patterns (fold > 2) of 24 identified proteins, seven down-regulated and 17 up-regulated. Most of these proteins were presumably associated with protein turnover, metabolism, structure and signal transduction. Protein-protein interactions (PPI) among these proteins, established by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, revealed that they participate in protein metabolic process, translation, and energy production. Furthermore, ubiquitin C (UbC) was predicted to be the controlling hub, suggesting the involvement of ubiquitin-proteasome system in modulating the pathogenic effect of CLC on DPC. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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10 pages, 741 KiB

Open AccessArticle

Au(I)-Catalyzed Annulation of Propargyl Amine with Aldehydes: One-Pot Cascade Synthesis of 2,5-Dimethylpyrazines

by Ji Su^1,2, Huixin Liu¹ and Ruimao Hua^1,*

¹ Department of Chemistry, Tsinghua University, Beijing 100084, China

² National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha 410004, China

Int. J. Mol. Sci. 2015, 16(2), 3599-3608; https://doi.org/10.3390/ijms16023599 - 5 Feb 2015

Cited by 26 | Viewed by 5776

Abstract

3-Substituted 2,5-dimethylpyrazines were synthesized in high yields via a one-pot cascade annulation of easily available propargyl amine with aldehydes catalyzed by Au(PPh₂Cy)Cl. Full article

(This article belongs to the Section Materials Science)

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17 pages, 966 KiB

Open AccessArticle

A Dynamic Combinatorial Approach for Identifying Side Groups that Stabilize DNA-Templated Supramolecular Self-Assemblies

by Delphine Paolantoni, Sonia Cantel, Pascal Dumy and Sébastien Ulrich^*

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université de Montpellier, ENSCM, Ecole Nationale Supérieure de Chimie de Montpellier, 8 Rue de l'Ecole Normale, Montpellier Cedex 5 34296, France

Int. J. Mol. Sci. 2015, 16(2), 3609-3625; https://doi.org/10.3390/ijms16023609 - 6 Feb 2015

Cited by 7 | Viewed by 6572

Abstract

DNA-templated self-assembly is an emerging strategy for generating functional supramolecular systems, which requires the identification of potent multi-point binding ligands. In this line, we recently showed that bis-functionalized guanidinium compounds can interact with ssDNA and generate a supramolecular complex through the recognition of [...] Read more.

DNA-templated self-assembly is an emerging strategy for generating functional supramolecular systems, which requires the identification of potent multi-point binding ligands. In this line, we recently showed that bis-functionalized guanidinium compounds can interact with ssDNA and generate a supramolecular complex through the recognition of the phosphodiester backbone of DNA. In order to probe the importance of secondary interactions and to identify side groups that stabilize these DNA-templated self-assemblies, we report herein the implementation of a dynamic combinatorial approach. We used an in situ fragment assembly process based on reductive amination and tested various side groups, including amino acids. The results reveal that aromatic and cationic side groups participate in secondary supramolecular interactions that stabilize the complexes formed with ssDNA. Full article

(This article belongs to the Special Issue Supramolecular Interactions)

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30 pages, 1928 KiB

Open AccessReview

Antimicrobial Polymeric Materials with Quaternary Ammonium and Phosphonium Salts

by Yan Xue^1,2, Huining Xiao^1,* and Yi Zhang³

¹ Department of Chemical Engineering, University of New Brunswick, Fredericton, NB E3B 5A3, Canada

² School of Chemistry and Chemical Engineering, Southwest Petroleum University, Chengdu 610500, China

³ School of Environment Science & Engineering, North China Electric Power University, Baoding 071003, China

Int. J. Mol. Sci. 2015, 16(2), 3626-3655; https://doi.org/10.3390/ijms16023626 - 6 Feb 2015

Cited by 491 | Viewed by 25707

Abstract

Polymeric materials containing quaternary ammonium and/or phosphonium salts have been extensively studied and applied to a variety of antimicrobial-relevant areas. With various architectures, polymeric quaternary ammonium/phosphonium salts were prepared using different approaches, exhibiting different antimicrobial activities and potential applications. This review focuses on [...] Read more.

Polymeric materials containing quaternary ammonium and/or phosphonium salts have been extensively studied and applied to a variety of antimicrobial-relevant areas. With various architectures, polymeric quaternary ammonium/phosphonium salts were prepared using different approaches, exhibiting different antimicrobial activities and potential applications. This review focuses on the state of the art of antimicrobial polymers with quaternary ammonium/phosphonium salts. In particular, it discusses the structure and synthesis method, mechanisms of antimicrobial action, and the comparison of antimicrobial performance between these two kinds of polymers. Full article

(This article belongs to the Special Issue Antimicrobial Polymers)

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21 pages, 3536 KiB

Open AccessArticle

Exploiting β-Cyclodextrin in Molecular Imprinting for Achieving Recognition of Benzylparaben in Aqueous Media

by Saliza Asman^1,2,†, Sharifah Mohamad^1,* and Norazilawati Muhamad Sarih^1,†

¹ Department of Chemistry, Faculty of Science, University of Malaya, Lembah Pantai 50603, Kuala Lumpur, Malaysia

² Department of Science and Mathematics, Faculty of Science, Technology and Human Development, University of Tun Hussein Onn Malaysia, Parit Raja 86400, Johor, Malaysia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3656-3676; https://doi.org/10.3390/ijms16023656 - 6 Feb 2015

Cited by 48 | Viewed by 8748

Abstract

The molecularly imprinted polymer (MIP) based on methacrylic acid functionalized β-cyclodextrin (MAA-β-CD) monomer was synthesized for the purpose of selective recognition of benzylparaben (BzP). The MAA-β-CD monomer was produced by bridging a methacrylic acid (MAA) and β-cyclodextrin (β-CD) using toluene-2,4-diisocyanate (TDI) by reacting [...] Read more.

The molecularly imprinted polymer (MIP) based on methacrylic acid functionalized β-cyclodextrin (MAA-β-CD) monomer was synthesized for the purpose of selective recognition of benzylparaben (BzP). The MAA-β-CD monomer was produced by bridging a methacrylic acid (MAA) and β-cyclodextrin (β-CD) using toluene-2,4-diisocyanate (TDI) by reacting the –OH group of MAA and one of the primary –OH groups of β-CD. This monomer comprised of triple interactions that included an inclusion complex, π–π interaction, and hydrogen bonding. To demonstrate β-CD performance in MIPs, two MIPs were prepared; molecularly imprinted polymer-methacrylic acid functionalized β-cyclodextrin, MIP(MAA-β-CD), and molecularly imprinted polymer-methacrylic acid, MIP(MAA); both prepared by a reversible addition fragmentation chain transfer polymerization (RAFT) in the bulk polymerization process. Both MIPs were characterized using the Fourier Transform Infrared Spectroscopy (FTIR), Field Emission Scanning Electron Microscopy (FESEM), and Brunauer-Emmett-Teller (BET). The presence of β-CD not only influenced the morphological structure, it also affected the specific surface area, average pore diameter, and total pore volume of the MIP. The rebinding of the imprinting effect was evaluated in binding experiments, which proved that the β-CD contributed significantly to the enhancement of the recognition affinity and selective adsorption of the MIP. Full article

(This article belongs to the Special Issue Supramolecular Interactions)

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23 pages, 4641 KiB

Open AccessArticle

Structural Analysis of the Complex between Penta-EF-Hand ALG-2 Protein and Sec31A Peptide Reveals a Novel Target Recognition Mechanism of ALG-2

by Takeshi Takahashi¹, Kyosuke Kojima¹, Wei Zhang¹, Kanae Sasaki¹, Masaru Ito¹, Hironori Suzuki^2,3, Masato Kawasaki², Soichi Wakatsuki^2,4, Terunao Takahara¹, Hideki Shibata¹ and Masatoshi Maki^1,*

¹ Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan

² Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan

³ Biomolecular Interaction Centre, School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch 8020, New Zealand

⁴ Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305-5126, USA

Int. J. Mol. Sci. 2015, 16(2), 3677-3699; https://doi.org/10.3390/ijms16023677 - 6 Feb 2015

Cited by 27 | Viewed by 11680

Abstract

ALG-2, a 22-kDa penta-EF-hand protein, is involved in cell death, signal transduction, membrane trafficking, etc., by interacting with various proteins in mammalian cells in a Ca²⁺-dependent manner. Most known ALG-2-interacting proteins contain proline-rich regions in which either PPYPXnYP [...] Read more.

ALG-2, a 22-kDa penta-EF-hand protein, is involved in cell death, signal transduction, membrane trafficking, etc., by interacting with various proteins in mammalian cells in a Ca²⁺-dependent manner. Most known ALG-2-interacting proteins contain proline-rich regions in which either PPYPXnYP (type 1 motif) or PXPGF (type 2 motif) is commonly found. Previous X-ray crystal structural analysis of the complex between ALG-2 and an ALIX peptide revealed that the peptide binds to the two hydrophobic pockets. In the present study, we resolved the crystal structure of the complex between ALG-2 and a peptide of Sec31A (outer shell component of coat complex II, COPII; containing the type 2 motif) and found that the peptide binds to the third hydrophobic pocket (Pocket 3). While amino acid substitution of Phe⁸⁵, a Pocket 3 residue, with Ala abrogated the interaction with Sec31A, it did not affect the interaction with ALIX. On the other hand, amino acid substitution of Tyr¹⁸⁰, a Pocket 1 residue, with Ala caused loss of binding to ALIX, but maintained binding to Sec31A. We conclude that ALG-2 recognizes two types of motifs at different hydrophobic surfaces. Furthermore, based on the results of serial mutational analysis of the ALG-2-binding sites in Sec31A, the type 2 motif was newly defined. Full article

(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)

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5 pages, 637 KiB

Open AccessEditorial

International Journal of Molecular Science 2015’s Best Paper Award

by Editorial Board of International Journal of Molecular Science

IJMS Editorial Office, MDPI AG, Klybeckstrasse 64, CH-4057 Basel, Switzerland

Int. J. Mol. Sci. 2015, 16(2), 3700-3704; https://doi.org/10.3390/ijms16023700 - 6 Feb 2015

Cited by 4 | Viewed by 7103

Abstract

The International Journal of Molecular Science has previously granted [1–3], and is continuing with our practice of granting, annual awards to recognize outstanding papers in the area of chemistry, molecular physics and molecular biology published in its journal. [...] Full article

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17 pages, 4708 KiB

Open AccessArticle

Identification of the Specific Interactors of the Human Lariat RNA Debranching Enzyme 1 Protein

by So Masaki^1,†, Rei Yoshimoto^2,3,4,†, Daisuke Kaida⁵, Asuka Hata¹, Takayuki Satoh⁵, Mutsuhito Ohno³ and Naoyuki Kataoka^1,3,6,*

¹ Medical Innovation Center, Laboratory for Malignancy Control Research, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan

² Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan

³ Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan

⁴ Division of Gene Expression Mechanism, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan

⁵ Frontier Research Core for Life Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, Japan

⁶ Medical Top Track Program, Medical Research Institute, Tokyo Dental and Medical University, Tokyo 113-8510, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3705-3721; https://doi.org/10.3390/ijms16023705 - 9 Feb 2015

Cited by 10 | Viewed by 7469

Abstract

In eukaryotes, pre-mRNA splicing is an essential step for gene expression. We have been analyzing post-splicing intron turnover steps in higher eukaryotes. Here, we report protein interaction between human Debranching enzyme 1 (hDbr1) and several factors found in the Intron Large (IL) complex, [...] Read more.

In eukaryotes, pre-mRNA splicing is an essential step for gene expression. We have been analyzing post-splicing intron turnover steps in higher eukaryotes. Here, we report protein interaction between human Debranching enzyme 1 (hDbr1) and several factors found in the Intron Large (IL) complex, which is an intermediate complex of the intron degradation pathway. The hDbr1 protein specifically interacts with xeroderma pigmentosum, complementeation group A (XPA)-binding protein 2 (Xab2). We also attempted to identify specific interactors of hDbr1. Co-immunoprecipitation experiments followed by mass spectrometry analysis identified a novel protein as one of the specific interactors of hDbr1. This protein is well conserved among many species and shows the highest similarity to yeast Drn1, so it is designated as human Dbr1 associated ribonuclease 1 (hDrn1). hDrn1 directly interacts with hDbr1 through protein–protein interaction. Furthermore, hDrn1 shuttles between the nucleus and the cytoplasm, as hDbr1 protein does. These findings suggest that hDrn1 has roles in both the nucleus and the cytoplasm, which are highly likely to involve hDbr1. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing)

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18 pages, 705 KiB

Open AccessArticle

Gender Differences in the VDR-FokI Polymorphism and Conventional Non-Genetic Risk Factors in Association with Lumbar Spine Pathologies in an Italian Case-Control Study

by Alessandra Colombini^1,*

, Marco Brayda-Bruno², Lucia Ferino³, Giovanni Lombardi¹

, Vincenzo Maione³, Giuseppe Banfi^1,4 and Sabina Cauci³

¹ IRCCS Galeazzi Orthopaedic Institute, via R. Galeazzi 4, 20161 Milan, Italy

² Department of Orthopedics and Traumatology—Vertebral surgery III—Scoliosis, IRCCS Galeazzi Orthopaedic Institute, via R. Galeazzi 4, 2016 Milan, Italy

³ Department of Medical and Biological Sciences, University of Udine, P.le Kolbe 4, 33100 Udine, Italy

⁴ Vita e Salute San Raffaele University, via Olgettina 58, 20132 Milan, Italy

Int. J. Mol. Sci. 2015, 16(2), 3722-3739; https://doi.org/10.3390/ijms16023722 - 9 Feb 2015

Cited by 31 | Viewed by 6174

Abstract

Recently, the FokI polymorphism (rs2228570) in the vitamin D receptor gene (VDR) and conventional risk factors were associated with spine disorders in the Italian population, but without gender analysis. Two-hundred and sixty-seven patients (149 males, 118 females) with lumbar spine disorders [...] Read more.

Recently, the FokI polymorphism (rs2228570) in the vitamin D receptor gene (VDR) and conventional risk factors were associated with spine disorders in the Italian population, but without gender analysis. Two-hundred and sixty-seven patients (149 males, 118 females) with lumbar spine disorders were assessed by magnetic resonance imaging (MRI) and 254 (127 males, 127 females) asymptomatic controls were enrolled. The exposure to putative risk factors was evaluated and FokI polymorphism was detected by PCR-restriction fragment length polymorphism (PCR-RFLP). An association between lumbar spine pathologies and higher than average age; overweight; family history; lower leisure physical activity; smoking habit; higher number of hours/day exposure to vibration and more sedentary or intense physical job demand was observed in male patients. In contrast, in females, only higher age, overweight, family history and lower leisure physical activity were risk factors. FF genotype was a 2-fold risk factor to develop discopathies and/or osteochondrosis concomitant with disc herniation for both gender patients, while heterozygous Ff was protective for females only. In males only ff genotype was protective for discopathies and/or osteochondrosis and F allele was a 2-fold risk factor for hernia; discopathies; discopathies and/or osteochondrosis. Sex-related differences in voluntary behaviors, exposure to environmental risks and genetic background could be crucial for a gender-differentiated management of patients with spine disorders. Full article

(This article belongs to the Special Issue Gene-Nutrient Interactions)

17 pages, 1130 KiB

Open AccessReview

Coronary CT Angiography in Managing Atherosclerosis

by Joachim Eckert^*, Marco Schmidt, Annett Magedanz, Thomas Voigtländer and Axel Schmermund

Cardioangiologisches Centrum Bethanien, Im Prüfling 23, D-60389 Frankfurt, Germany

Int. J. Mol. Sci. 2015, 16(2), 3740-3756; https://doi.org/10.3390/ijms16023740 - 9 Feb 2015

Cited by 48 | Viewed by 11797

Abstract

Invasive coronary angiography (ICA) was the only method to image coronary arteries for a long time and is still the gold-standard. Technology of noninvasive imaging by coronary computed-tomography angiography (CCTA) has experienced remarkable progress during the last two decades. It is possible to [...] Read more.

Invasive coronary angiography (ICA) was the only method to image coronary arteries for a long time and is still the gold-standard. Technology of noninvasive imaging by coronary computed-tomography angiography (CCTA) has experienced remarkable progress during the last two decades. It is possible to visualize atherosclerotic lesions in the vessel wall in contrast to “lumenography” performed by ICA. Coronary artery disease can be ruled out by CCTA with excellent accuracy. The degree of stenoses is, however, often overestimated which impairs specificity. Atherosclerotic lesions can be characterized as calcified, non-calcified and partially calcified. Calcified plaques are usually quantified using the Agatston-Score. Higher scores are correlated with worse cardiovascular outcome and increased risk of cardiac events. For non-calcified or partially calcified plaques different angiographic findings like positive remodelling, a large necrotic core or spotty calcification more frequently lead to myocardial infarctions. CCTA is an important tool with increasing clinical value for ruling out coronary artery disease or relevant stenoses as well as for advanced risk stratification. Full article

(This article belongs to the Special Issue Atherosclerosis and Vascular Imaging)

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12 pages, 928 KiB

Open AccessArticle

The Role of hOGG1 C1245G Polymorphism in the Susceptibility to Lupus Nephritis and Modulation of the Plasma 8-OHdG in Patients with Systemic Lupus Erythematosus

by Hui-Ting Lee^1,2,3,4, Chen-Sung Lin^1,2,5, Chyou-Shen Lee^3,4,6, Chang-Youh Tsai^1,2,7,*

and Yau-Huei Wei^1,2,3,8,*

¹ Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan

² Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan

³ Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan

⁴ Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 104, Taiwan

⁵ Division of Thoracic Surgery, Taipei Hospital, Ministry of Health and Welfare, New Taipei City 242, Taiwan

⁶ Mackay Junior College of Medicine, Nursing, and Management, New Taipei City 252, Taiwan

⁷ Division of Allergy, Immunology and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan

⁸ Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan

Int. J. Mol. Sci. 2015, 16(2), 3757-3768; https://doi.org/10.3390/ijms16023757 - 9 Feb 2015

Cited by 12 | Viewed by 6139

Abstract

We investigated whether the C1245G polymorphism of human 8-oxoguanine glycosylase 1 (hOGG1) gene confers the susceptibility to systemic lupus erythematosus (SLE) occurrence of lupus nephritis and affects the plasma level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in patients with SLE. A total of 45 [...] Read more.

We investigated whether the C1245G polymorphism of human 8-oxoguanine glycosylase 1 (hOGG1) gene confers the susceptibility to systemic lupus erythematosus (SLE) occurrence of lupus nephritis and affects the plasma level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in patients with SLE. A total of 45 healthy controls and 85 SLE patients were recruited. The C1245G polymorphism of the hOGG1 gene was determined by direct sequencing. The frequency of occurrence of the hOGG1 1245 GG genotype in SLE patients was 31.8% (27/85), which is lower than that of healthy controls of 53.3% (24/45). Thirty-three (33/85, 38.8%) SLE patients developed lupus nephritis. Significantly, SLE patients harboring the hOGG1 1245 GG genotype had a higher incidence to develop lupus nephritis than did those harboring the hOGG1 1245 CC or CG genotype (15/27, 55.6% vs.18/58, 31.0%, p = 0.031). Divided into subgroups, SLE patients harboring the hOGG1 1245 GG genotype had the highest plasma levels of 8-OHdG among patients with all genotypes, with regard to the coexistence of lupus nephritis (p = 0.020, ANOVA), including those with nephritis harboring the hOGG1 1245 CC or CG genotypes (p = 0.037), those without nephritis harboring the hOGG1 1245 GG genotype (p = 0.050), and those without nephritis harboring the hOGG1 1245 CC or CG genotype (p = 0.054). We conclude that the C1245G polymorphism of hOGG1 may be one of the factors that confer the susceptibility to lupus nephritis and modulate the plasma level of 8-OHdG in patients with SLE. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in the Pathogenesis of Systemic Lupus Erythematosus)

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14 pages, 1092 KiB

Open AccessArticle

Thermochemical Pretreatments of Organic Fraction of Municipal Solid Waste from a Mechanical-Biological Treatment Plant

by Carlos José Alvarez-Gallego¹, Luis Alberto Fdez-Güelfo², María de los Angeles Romero Aguilar¹ and Luis Isidoro Romero García^1,*

¹ Department of Chemical Engineering and Food Technology, Faculty of Science, University of Cádiz, Puerto Real 11510, Cádiz, Spain

² Department of Environmental Technologies, CASEM building, University of Cádiz, Puerto Real 11510, Cádiz, Spain

Int. J. Mol. Sci. 2015, 16(2), 3769-3782; https://doi.org/10.3390/ijms16023769 - 9 Feb 2015

Cited by 16 | Viewed by 5881

Abstract

The organic fraction of municipal solid waste (OFMSW) usually contains high lignocellulosic and fatty fractions. These fractions are well-known to be a hard biodegradable substrate for biological treatments and its presence involves limitations on the performance of anaerobic processes. To avoid this, thermochemical [...] Read more.

The organic fraction of municipal solid waste (OFMSW) usually contains high lignocellulosic and fatty fractions. These fractions are well-known to be a hard biodegradable substrate for biological treatments and its presence involves limitations on the performance of anaerobic processes. To avoid this, thermochemical pretreatments have been applied on the OFMSW coming from a full-scale mechanical-biological treatment (MBT) plant, in order to pre-hydrolyze the waste and improve the organic matter solubilisation. To study the solubilisation yield, the increments of soluble organic matter have been measured in terms of dissolved organic carbon (DOC), soluble chemical oxygen demand (sCOD), total volatile fatty acids (TVFA) and acidogenic substrate as carbon (ASC). The process variables analyzed were temperature, pressure and NaOH dosage. The levels of work for each variable were three: 160–180–200 °C, 3.5–5.0–6.5 bar and 2–3–4 g NaOH/L. In addition, the pretreatment time was also modified among 15 and 120 min. The best conditions for organic matter solubilisation were 160 °C, 3 g NaOH/L, 6.5 bar and 30 min, with yields in terms of DOC, sCOD_,TVFA and ASC of 176%, 123%, 119% and 178% respectively. Thus, predictably the application of this pretreatment in these optimum conditions could improve the H₂ production during the subsequent Dark Fermentation process. Full article

(This article belongs to the Special Issue Green Chemistry and the Biorefinery)

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21 pages, 19537 KiB

Open AccessArticle

Expression of RCAS1 Correlates with Urothelial Bladder Cancer Malignancy

by Wojciech Jóźwicki^1,2,*, Anna A. Brożyna^1,2, Jerzy Siekiera³ and Andrzej T. Slominski^4,5

¹ Department of Tumor Pathology and Pathomorphology, the Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Romanowska Street 2, Bydgoszcz 85-796, Poland

² Department of Tumor Pathology and Pathomorphology, the Franciszek Łukaszczyk Oncology Centre, Romanowska Street 2, Bydgoszcz 85-796, Poland

³ Department of Urology, the Franciszek Łukaszczyk Oncology Centre, Romanowska Street 2, Bydgoszcz 85-796, Poland

⁴ Department of Pathology and Laboratory Medicine, University of Tennessee HSC, 930 Madison Avenue, Memphis, TN 38163, USA

⁵ Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Int. J. Mol. Sci. 2015, 16(2), 3783-3803; https://doi.org/10.3390/ijms16023783 - 10 Feb 2015

Cited by 8 | Viewed by 5575

Abstract

RCAS1 is a protein that participates in regulation of the tumor microenvironment and its immune responses, all in order to evade the immune system. The aim of this study was to analyze RCAS1 expression in urothelial bladder cancer cells (and in fibroblasts and [...] Read more.

RCAS1 is a protein that participates in regulation of the tumor microenvironment and its immune responses, all in order to evade the immune system. The aim of this study was to analyze RCAS1 expression in urothelial bladder cancer cells (and in fibroblasts and macrophages of the tumor stroma) and its relationship with the histological pattern of malignancy. Eighty-three postcystectomy patients were enrolled. We analyzed the histological maturity (grade), progress (pT stage), tissue invasion type (TIT), nonclassic differentiation number (NDN), and the ability to metastasize (pN). The expression of RCAS1 protein was analyzed by immunohistochemistry. Indicators of histological malignancy were observed solely in association with the RCAS1 expression in cells in the border parts (BPs) of the tumor. Histological malignancy of the tumor, indicated by the pT and pN, and metastasis-free survival time, correlated significantly with RCAS1 expression in tumor neoplastic cells, whereas malignancy determined by grade, TIT, and NDN correlated with RCAS1 expression in fibroblasts and macrophages in the tumor microenvironment. These findings suggest that the increased RCAS1 expression depends on its cellular source and that RCAS1 expression itself is a component of various signaling pathways. The immune escape occurs within the tumor BPs, where the increase in the RCAS1 expression occurs within tumor cells and stromal cells in its microenvironment. We conclude that the histological pattern of tumor malignancy, indicated by grade, TIT, NDN, pT, and pN is a morphological indicator of immune escape. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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16 pages, 3861 KiB

Open AccessArticle

Experimental and Theoretical Study of O-Substituent Effect on the Fluorescence of 8-Hydroxyquinoline

by Mohie E. M. Zayed¹, Reda M. El-Shishtawy^1,2,*

, Shaaban A. Elroby^1,3

, Abdullah Y. Obaid¹ and Zahra M. Al-amshany¹

¹ Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah B.O.208203, Saudi Arabia

² Dyeing, Printing and Textile Auxiliaries Department, Textile Research Division, National Research Center, Dokki, Cairo 12622, Egypt

³ Chemistry Department, Faculty of Science, Beni Suef University, Beni Suef 6251, Egypt

Int. J. Mol. Sci. 2015, 16(2), 3804-3819; https://doi.org/10.3390/ijms16023804 - 10 Feb 2015

Cited by 5 | Viewed by 11012

Abstract

The synthesis and characterization of different ether and ester derivatives of 8-hydroxyquinoline have been made. UV-visible and fluorescence spectra of these compounds have revealed spectral dependence on both solvent and O-substituent. The fluorescence intensity of ether derivatives revealed higher intensity for 8-octyloxyquinoline compared [...] Read more.

The synthesis and characterization of different ether and ester derivatives of 8-hydroxyquinoline have been made. UV-visible and fluorescence spectra of these compounds have revealed spectral dependence on both solvent and O-substituent. The fluorescence intensity of ether derivatives revealed higher intensity for 8-octyloxyquinoline compared with 8-methoxyquinoline, whereas those of ester derivatives had less fluorescence than 8-hydroxyquinoline. Theoretical calculations based on Time-dependent density functional theory (TD-DFT) were carried out for the quinolin-8-yl benzoate (8-OateQ) compound to understand the effect of O-substituent on the electronic absorption of 8-hydroxyquinaline (8-HQ). The calculations revealed comparable results with those obtained from the experimental data. Optimized geometrical structure was calculated with DFT at B3LYP/6-311++G** level of theory. The results indicated that 8-OateQ is not a coplanar structure. The absorption spectra of the compound were computed in gas-phase and solvent using B3LYP and CAM-B3LYP methods with 6-311++G ** basis set. The agreement between calculated and experimental wavelengths was very good at CAM-B3LYP/6-311++G** level of theory. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2015)

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11 pages, 711 KiB

Open AccessArticle

Diabetes Mellitus Increases Severity of Thrombocytopenia in Dengue-Infected Patients

by Chung-Yuan Chen^1,†, Mei-Yueh Lee^2,†, Kun-Der Lin³, Wei-Hao Hsu², Yaun-Jinn Lee⁴, Pi-Jung Hsiao^3,‡ and Shyi-Jang Shin^3,5,*,‡

¹ Chin Pin Clinic, Kaohsiung 807, Taiwan

² Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan

³ Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

⁴ Lee's Clinic, Ping Tung 900, Taiwan

⁵ Center for Lipid and Glycomedicine Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan

^† These authors contributed equally to this work.

^‡ These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3820-3830; https://doi.org/10.3390/ijms16023820 - 10 Feb 2015

Cited by 28 | Viewed by 8769

Abstract

Background: Diabetes mellitus is known to exacerbate bacterial infection, but its effect on the severity of viral infection has not been well studied. The severity of thrombocytopenia is an indicator of the severity of dengue virus infection. We investigated whether diabetes is associated [...] Read more.

Background: Diabetes mellitus is known to exacerbate bacterial infection, but its effect on the severity of viral infection has not been well studied. The severity of thrombocytopenia is an indicator of the severity of dengue virus infection. We investigated whether diabetes is associated with thrombocytopenia in dengue-infected patients. Methods: We studied clinical characteristics of 644 patients with dengue infection at a university hospital during the epidemic on 1 June 2002 to 31 December 2002 in Taiwan. Platelet counts and biochemical data were compared between patients with and without diabetes. Potential risk factors associated with thrombocytopenia were explored using regression analyses. Results: Dengue-infected patients with diabetes had lower platelet counts than patients without diabetes during the first three days (54.54 ± 51.69 vs. 86.58 ± 63.4 (p ≤ 0.001), 43.98 ± 44.09 vs. 64.52 ± 45.06 (p = 0.002), 43.86 ± 35.75 vs. 62.72 ± 51.2 (p = 0.012)). Diabetes mellitus, death, dengue shock syndrome (DSS) and dengue hemorrhagic fever (DHF) and increased glutamic-pyruvate transaminase (GPT) levels were significantly associated with lower platelet counts during the first day of hospitalization for dengue fever with regression β of −13.981 (95% confidence interval (CI) −27.587, −0.374), −26.847 (95% CI −37.562, −16.132), and 0.054 (95% CI 0.015, 0.094) respectively. Older age, hypoalbuminemia, and hypertriglyceridemia were independently correlated with thrombocytopenia in dengue patients with or without diabetes with regression β of −2.947 (p = 0.004), 2.801 (p = 0.005), and −3.568 (p ≤ 0.001), respectively. Diabetic patients with dengue had a higher rate of dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) than non-diabetic patients. They also had lower blood albumin, were older, and higher triglyceride levels. Older age, hypoalbuminemia, and hypertriglyceridemia were independently correlated with thrombocytopenia in dengue patients. Conclusions: Dengue patients with diabetes tended to have more severe thrombocytopenia and were more likely to have DHF/DSS. Older age, hypoalbuminemia, and hypertriglyceridemia were independently associated with more severe thrombocytopenia in dengue patients. Full article

(This article belongs to the Section Biochemistry)

25 pages, 741 KiB

Open AccessReview

Fatty Acid Signaling: The New Function of Intracellular Lipases

by Zuzana Papackova^† and Monika Cahova^*,†

¹ Centre for Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech Republic

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3831-3855; https://doi.org/10.3390/ijms16023831 - 10 Feb 2015

Cited by 107 | Viewed by 9364

Abstract

Until recently, intracellular triacylglycerols (TAG) stored in the form of cytoplasmic lipid droplets have been considered to be only passive “energy conserves”. Nevertheless, degradation of TAG gives rise to a pleiotropic spectrum of bioactive intermediates, which may function as potent co-factors of transcription [...] Read more.

Until recently, intracellular triacylglycerols (TAG) stored in the form of cytoplasmic lipid droplets have been considered to be only passive “energy conserves”. Nevertheless, degradation of TAG gives rise to a pleiotropic spectrum of bioactive intermediates, which may function as potent co-factors of transcription factors or enzymes and contribute to the regulation of numerous cellular processes. From this point of view, the process of lipolysis not only provides energy-rich equivalents but also acquires a new regulatory function. In this review, we will concentrate on the role that fatty acids liberated from intracellular TAG stores play as signaling molecules. The first part provides an overview of the transcription factors, which are regulated by fatty acids derived from intracellular stores. The second part is devoted to the role of fatty acid signaling in different organs/tissues. The specific contribution of free fatty acids released by particular lipases, hormone-sensitive lipase, adipose triacylglycerol lipase and lysosomal lipase will also be discussed. Full article

(This article belongs to the Section Biochemistry)

14 pages, 1287 KiB

Open AccessArticle

Exploring Prostate Cancer Genome Reveals Simultaneous Losses of PTEN, FAS and PAPSS2 in Patients with PSA Recurrence after Radical Prostatectomy

by Chinyere Ibeawuchi¹, Hartmut Schmidt², Reinhard Voss³, Ulf Titze⁴, Mahmoud Abbas⁵, Joerg Neumann⁶, Elke Eltze⁷, Agnes Marije Hoogland⁸, Guido Jenster⁹, Burkhard Brandt¹⁰ and Axel Semjonow^1,*

¹ Prostate Center, Department of Urology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebaeude 1A, Muenster D-48149, Germany

² Center for Laboratory Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebaeude 1A, Muenster D-48149, Germany

³ Interdisciplinary Center for Clinical Research, University of Muenster, Albert-Schweitzer-Campus 1, Gebaeude D3, Domagkstrasse 3, Muenster D-48149, Germany

⁴ Pathology, Lippe Hospital Detmold, Röntgenstrasse 18, Detmold D-32756, Germany

⁵ Institute of Pathology, Mathias-Spital-Rheine, Frankenburg Street 31, Rheine D-48431, Germany

⁶ Institute of Pathology, Klinikum Osnabrueck, Am Finkenhuegel 1, Osnabrueck D-49076, Germany

⁷ Institute of Pathology, Saarbrücken-Rastpfuhl, Rheinstrasse 2, Saarbrücken D-66113, Germany

⁸ Department of Pathology, Erasmus Medical Center, 's-Gravendijkwal 230, 3015-CE Rotterdam, The Netherlands

⁹ Department of Urology, Erasmus Medical Center, 's-Gravendijkwal 230, 3015-CE Rotterdam, The Netherlands

¹⁰ Institute for Clinical Chemistry, University Clinic Schleswig-Holsteins, Arnold-Heller-Strasse 3, Haus 17, Kiel D-24105, Germany

Int. J. Mol. Sci. 2015, 16(2), 3856-3869; https://doi.org/10.3390/ijms16023856 - 11 Feb 2015

Cited by 17 | Viewed by 9285

Abstract

The multifocal nature of prostate cancer (PCa) creates a challenge to patients’ outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients’ clinico-pathological [...] Read more.

The multifocal nature of prostate cancer (PCa) creates a challenge to patients’ outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients’ clinico-pathological information, specific prognostic biomarker can be identified. Our study utilized the Affymetrix SNP 6.0 Genome-wide assay to investigate forty-three fresh frozen PCa tissue foci from twenty-three patients. With a long clinical follow-up period that ranged from 2.0–9.7 (mean 5.4) years, copy number variation (CNV) data was evaluated for association with patients’ PSA status during follow-up. From our results, the loss of unique genes on 10q23.31 and 10q23.2–10q23.31 were identified to be significantly associated to PSA recurrence (p < 0.05). The implication of PTEN and FAS loss (10q23.31) support previous reports due to their critical roles in prostate carcinogenesis. Furthermore, we hypothesize that the PAPSS2 gene (10q23.2–10q23.31) may be functionally relevant in post-operative PSA recurrence because of its reported role in androgen biosynthesis. It is suggestive that the loss of the susceptible region on chromosome 10q, which implicates PTEN, FAS and PAPSS2 may serve as genetic predictors of PSA recurrence after radical prostatectomy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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15 pages, 873 KiB

Open AccessArticle

Autism and Intellectual Disability Associated with Mitochondrial Disease and Hyperlactacidemia

by José Guevara-Campos¹, Lucía González-Guevara² and Omar Cauli^3,*

¹ Felipe Guevara Rojas" Hospital, Pediatrics Service, University of Oriente, El Tigre-Anzoátegui, 6034 Venezuela, Spain

² Felipe Guevara Rojas" Hospital, Epilepsy and Encephalography Unit, El Tigre-Anzoátegui, 6034 Venezuela, Spain

³ Department of Nursing, University of Valencia, 46010 Valencia, Spain

Int. J. Mol. Sci. 2015, 16(2), 3870-3884; https://doi.org/10.3390/ijms16023870 - 11 Feb 2015

Cited by 24 | Viewed by 11153

Abstract

Autism spectrum disorder (ASD) with intellectual disability (ID) is a life-long debilitating condition, which is characterized by cognitive function impairment and other neurological signs. Children with ASD-ID typically attain motor skills with a significant delay. A sub-group of ASD-IDs has been linked to [...] Read more.

Autism spectrum disorder (ASD) with intellectual disability (ID) is a life-long debilitating condition, which is characterized by cognitive function impairment and other neurological signs. Children with ASD-ID typically attain motor skills with a significant delay. A sub-group of ASD-IDs has been linked to hyperlactacidemia and alterations in mitochondrial respiratory chain activity. The objective of this report is to describe the clinical features of patients with these comorbidities in order to shed light on difficult diagnostic and therapeutic approaches in such patients. We reported the different clinical features of children with ID associated with hyperlactacidemia and deficiencies in mitochondrial respiratory chain complex II–IV activity whose clinical presentations are commonly associated with the classic spectrum of mitochondrial diseases. We concluded that patients with ASD and ID presenting with persistent hyperlactacidemia should be evaluated for mitochondrial disorders. Administration of carnitine, coenzyme Q10, and folic acid is partially beneficial, although more studies are needed to assess the efficacy of this vitamin/cofactor treatment combination. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders)

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10 pages, 708 KiB

Open AccessArticle

A Variant in the Osteoprotegerin Gene Is Associated with Coronary Atherosclerosis in Patients with Rheumatoid Arthritis: Results from a Candidate Gene Study

by Cecilia P. Chung¹, Joseph F. Solus¹, Annette Oeser¹, Chun Li², Paolo Raggi^3,*, Jeffrey R. Smith¹ and C. Michael Stein¹

¹ Departments of Medicine and Biostatistics, Vanderbilt University, Nashville, TN 37232, USA

² Biostatistics, Vanderbilt University, Nashville, TN 37232, USA

³ Mazankowski Alberta Heart Institute, Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada

Int. J. Mol. Sci. 2015, 16(2), 3885-3894; https://doi.org/10.3390/ijms16023885 - 11 Feb 2015

Cited by 12 | Viewed by 6555

Abstract

Objective: Patients with rheumatoid arthritis (RA) have accelerated atherosclerosis, but there is limited information about the genetic contribution to atherosclerosis in this population. Therefore, we examined the association between selected genetic polymorphisms and coronary atherosclerosis in patients with RA. Methods: Genotypes for single-nucleotide [...] Read more.

Objective: Patients with rheumatoid arthritis (RA) have accelerated atherosclerosis, but there is limited information about the genetic contribution to atherosclerosis in this population. Therefore, we examined the association between selected genetic polymorphisms and coronary atherosclerosis in patients with RA. Methods: Genotypes for single-nucleotide polymorphisms (SNPs) in 152 candidate genes linked with autoimmune or cardiovascular risk were measured in 140 patients with RA. The association between the presence of coronary artery calcium (CAC) and SNP allele frequency was assessed by logistic regression with adjustment for age, sex, and race. To adjust for multiple comparisons, a false discovery rate (FDR) threshold was set at 20%. Results: Patients with RA were 54 ± 11 years old and predominantly Caucasian (89%) and female (69%). CAC was present in 70 patients (50%). A variant in rs2073618 that encodes an Asn3Lys missense substitution in the osteoprotegerin gene (OPG, TNFRSF11B) was significantly associated with the presence of CAC (OR = 4.09, p < 0.00026) and withstands FDR correction. Conclusion: Our results suggest that a polymorphism of the TNFRSF11B gene, which encodes osteoprotegerin, is associated with the presence of coronary atherosclerosis in patients with RA. Replication of this finding in independent validation cohorts will be of interest. Full article

(This article belongs to the Special Issue Atherosclerosis and Vascular Imaging)

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20 pages, 699 KiB

Open AccessReview

Nutritionally Enhanced Food Crops; Progress and Perspectives

by Kathleen L. Hefferon

Cell and Systems Biology, University of Toronto, Toronto, ON, M5S 1A1, Canada

Int. J. Mol. Sci. 2015, 16(2), 3895-3914; https://doi.org/10.3390/ijms16023895 - 11 Feb 2015

Cited by 154 | Viewed by 27234

Abstract

Great progress has been made over the past decade with respect to the application of biotechnology to generate nutritionally improved food crops. Biofortified staple crops such as rice, maize and wheat harboring essential micronutrients to benefit the world’s poor are under development as [...] Read more.

Great progress has been made over the past decade with respect to the application of biotechnology to generate nutritionally improved food crops. Biofortified staple crops such as rice, maize and wheat harboring essential micronutrients to benefit the world’s poor are under development as well as new varieties of crops which have the ability to combat chronic disease. This review discusses the improvement of the nutritional status of crops to make a positive impact on global human health. Several examples of nutritionally enhanced crops which have been developed using biotechnological approaches will be discussed. These range from biofortified crops to crops with novel abilities to fight disease. The review concludes with a discussion of hurdles faced with respect to public perception, as well as directions of future research and development for nutritionally enhanced food crops. Full article

(This article belongs to the Special Issue Pharmaceuticals and Nutraceuticals by Molecular Farming)

17 pages, 2774 KiB

Open AccessArticle

Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach

by Mohamed A. Abdallah Elbadawi^1,†, Mohamed Khalid Alhaj Awadalla^2,*,†, Muzamil Mahdi Abdel Hamid³, Magdi Awadalla Mohamed⁴ and Talal Ahmed Awad⁵

¹ Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum 11111, Sudan

² College of Pharmacy, University of Hail, Hail 81451, Saudi Arabia

³ Department of Parasitology and Medical Entomology, Institute of Endemic Diseases, University of Khartoum, Khartoum 11111, Sudan

⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Khartoum, Khartoum 11111, Sudan

⁵ Medicinal and Aromatic Plants Research Institute, National Centre of Research, Khartoum 11111, Sudan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 3915-3931; https://doi.org/10.3390/ijms16023915 - 11 Feb 2015

Cited by 12 | Viewed by 11030

Abstract

A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations [...] Read more.

A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1. Full article

(This article belongs to the Section Molecular Recognition)

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23 pages, 829 KiB

Open AccessReview

Tumor Immunotargeting Using Innovative Radionuclides

by Françoise Kraeber-Bodéré^1,2,3,*, Caroline Rousseau^1,3, Caroline Bodet-Milin^1,2, Cédric Mathieu², François Guérard¹, Eric Frampas^1,4, Thomas Carlier^1,2, Nicolas Chouin⁵, Ferid Haddad⁶, Jean-François Chatal⁶, Alain Faivre-Chauvet^1,2, Michel Chérel^1,3 and Jacques Barbet^1,6

¹ Nantes-Angers Cancer Research Center (CRCNA), University of Nantes, Inserm UMR 892, CNRS UMR 6299, Nantes 44007, France

² Department of Nuclear Medicine, University Hospital, Nantes 44093, France

³ Department of Nuclear Medicine, Institut de Cancérologie de l'Ouest (ICO)-Site Gauducheau, Saint-Herblain 44805, France

⁴ Department of Radiology, University Hospital, Nantes 44093, France

⁵ AMAROC, ONIRIS, Nantes 44300, France

⁶ Physics Department, Groupement d'Intérêt Public Arronax, Nantes 44817, France

Int. J. Mol. Sci. 2015, 16(2), 3932-3954; https://doi.org/10.3390/ijms16023932 - 11 Feb 2015

Cited by 46 | Viewed by 9886

Abstract

This paper reviews some aspects and recent developments in the use of antibodies to target radionuclides for tumor imaging and therapy. While radiolabeled antibodies have been considered for many years in this context, only a few have reached the level of routine clinical [...] Read more.

This paper reviews some aspects and recent developments in the use of antibodies to target radionuclides for tumor imaging and therapy. While radiolabeled antibodies have been considered for many years in this context, only a few have reached the level of routine clinical use. However, alternative radionuclides, with more appropriate physical properties, such as lutetium-177 or copper-67, as well as alpha-emitting radionuclides, including astatine-211, bismuth-213, actinium-225, and others are currently reviving hopes in cancer treatments, both in hematological diseases and solid tumors. At the same time, PET imaging, with short-lived radionuclides, such as gallium-68, fluorine-18 or copper-64, or long half-life ones, particularly iodine-124 and zirconium-89 now offers new perspectives in immuno-specific phenotype tumor imaging. New antibody analogues and pretargeting strategies have also considerably improved the performances of tumor immunotargeting and completely renewed the interest in these approaches for imaging and therapy by providing theranostics, companion diagnostics and news tools to make personalized medicine a reality. Full article

(This article belongs to the Special Issue Frontiers of Radioimmunotherapy)

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15 pages, 1118 KiB

Open AccessArticle

Multifunctional Composites of Chiral Valine Derivative Schiff Base Cu(II) Complexes and TiO₂

by Yuki Takeshita, Kazuya Takakura and Takashiro Akitsu^*

Department of Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan

Int. J. Mol. Sci. 2015, 16(2), 3955-3969; https://doi.org/10.3390/ijms16023955 - 12 Feb 2015

Cited by 13 | Viewed by 6666

Abstract

We have prepared four new Cu(II) complexes containing valine moieties with imidazole ligands at the fourth coordination sites and examined their photo-induced reactions with TiO₂ in order of understanding the reaction mechanisms. Under a nitrogen atmosphere, the intermolecular electron transfer reactions (essentially [...] Read more.

We have prepared four new Cu(II) complexes containing valine moieties with imidazole ligands at the fourth coordination sites and examined their photo-induced reactions with TiO₂ in order of understanding the reaction mechanisms. Under a nitrogen atmosphere, the intermolecular electron transfer reactions (essentially supramolecular interactions) of these systems, which resulted in the reduction of Cu(II) species to Cu(I) ones, occurred after UV light irradiation. In this study, we have investigated the conditions of the redox reactions in view of substituent effects of aldehyde moieties. The results of cyclic voltammetry (CV) on an rotating ring-disk electrode (RRDE) suggested that the substitution effects and redox potentials were correlated. Density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were also performed to simulate the UV–Vis and circular dichroism (CD) spectra; the results revealed a reasonably good correlation between the substituent effects and the highest occupied molecular orbitals and the lowest unoccupied molecular orbitals (HOMO-LUMO) gaps associated with the most intense transition bands. In addition, we summarized the substitution effects of Cu(II) complexes for their corresponding UV light-induced reactions. Full article

(This article belongs to the Special Issue Supramolecular Interactions)

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10 pages, 930 KiB

Open AccessReview

Regulation of Translation Factor EEF1D Gene Function by Alternative Splicing

by Taku Kaitsuka¹ and Masayuki Matsushita^2,*

¹ Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan

² Department of Molecular and Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan

Int. J. Mol. Sci. 2015, 16(2), 3970-3979; https://doi.org/10.3390/ijms16023970 - 12 Feb 2015

Cited by 15 | Viewed by 7272

Abstract

Alternative splicing is an exquisite mechanism that allows one coding gene to have multiple functions. The alternative splicing machinery is necessary for proper development, differentiation and stress responses in a variety of organisms, and disruption of this machinery is often implicated in human [...] Read more.

Alternative splicing is an exquisite mechanism that allows one coding gene to have multiple functions. The alternative splicing machinery is necessary for proper development, differentiation and stress responses in a variety of organisms, and disruption of this machinery is often implicated in human diseases. Previously, we discovered a long form of eukaryotic elongation factor 1Bδ (eEF1Bδ; this long-form eEF1Bδ results from alternative splicing of EEF1D transcripts and regulates the cellular stress response by transcriptional activation, not translational enhancement, of heat-shock responsive genes. In this review, we discuss the molecular function of EEF1D alternative splicing products and the estimated implication of human diseases. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing)

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10 pages, 709 KiB

Open AccessArticle

Isolation and Cytotoxicity Evaluation of the Chemical Constituents from Cephalantheropsis gracilis

by Chi-Fen Chang¹, Yu-Lin Hsu², Chao-Ying Lee³, Chia-Hua Wu³, Yang-Chang Wu^3,4,5,6,7,* and Ta-Hsien Chuang^3,4,*

¹ Department of Anatomy, School of Medicine, China Medical University, Taichung 40402, Taiwan

² Department of Chemistry, National Cheng Kung University, Tainan 70101, Taiwan

³ School of Pharmacy, China Medical University, Taichung 40402, Taiwan

⁴ Research Center for Chinese Herbal Medicine, China Medical University, Taichung 40402, Taiwan

⁵ Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 40402, Taiwan

⁶ Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

⁷ Center of Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan

Int. J. Mol. Sci. 2015, 16(2), 3980-3989; https://doi.org/10.3390/ijms16023980 - 12 Feb 2015

Cited by 54 | Viewed by 6158

Abstract

Cephalantheropsis gracilis afforded five new compounds: cephalanthrin-A (1), cephalanthrin-B (2), cephathrene-A (3), cephathrene-B (4), methyl 2-(aminocarbonyl) phenylcarbamate (5), and 52 known compounds. The structures of the new compounds were determined by spectroscopic analysis. [...] Read more.

Cephalantheropsis gracilis afforded five new compounds: cephalanthrin-A (1), cephalanthrin-B (2), cephathrene-A (3), cephathrene-B (4), methyl 2-(aminocarbonyl) phenylcarbamate (5), and 52 known compounds. The structures of the new compounds were determined by spectroscopic analysis. Among the compounds isolated, tryptanthrin (6), phaitanthrin A (7), cephalinone D (19), and flavanthrin (30) showed significant cytotoxicity against MCF-7, NCI-H460, and SF-268 cell lines. Full article

(This article belongs to the Section Biochemistry)

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6 pages, 983 KiB

Open AccessCommunication

Development of Biodegradable Nanocarriers Loaded with a Monoclonal Antibody

by Andrew Gdowski^1,2, Amalendu Ranjan^1,3, Anindita Mukerjee^1,3 and Jamboor Vishwanatha^1,3,*

¹ Department of Molecular and Medical Genetics, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA

² Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA

³ Institute of Cancer Research, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA

Int. J. Mol. Sci. 2015, 16(2), 3990-3995; https://doi.org/10.3390/ijms16023990 - 12 Feb 2015

Cited by 35 | Viewed by 7317

Abstract

Treatments utilizing monoclonal antibody therapeutics against intracellular protein-protein interactions in cancer cells have been hampered by several factors, including poor intracellular uptake and rapid lysosomal degradation. Our current work examines the feasibility of encapsulating monoclonal antibodies within poly(lactic-co-glycolic acid) (PLGA) nanoparticles [...] Read more.

Treatments utilizing monoclonal antibody therapeutics against intracellular protein-protein interactions in cancer cells have been hampered by several factors, including poor intracellular uptake and rapid lysosomal degradation. Our current work examines the feasibility of encapsulating monoclonal antibodies within poly(lactic-co-glycolic acid) (PLGA) nanoparticles using a water/oil/water double emulsion solvent evaporation technique. This method can be used to prepare protective polymeric nanoparticles for transporting functional antibodies to the cytoplasmic compartment of cancer cells. Nanoparticles were formulated and then characterized using a number of physical and biological parameters. The average nanoparticle size ranged from 221 to 252 nm with a low polydispersity index. Encapsulation efficiency of 16%–22% and antibody loading of 0.3%–1.12% were observed. The antibody molecules were released from the nanoparticles in a sustained manner and upon release maintained functionality. Our studies achieved successful formulation of antibody loaded polymeric nanoparticles, thus indicating that a PLGA-based antibody nanoformulation is a promising intracellular delivery vehicle for a large number of new intracellular antibody targets in cancer cells. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles 2014)

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11 pages, 2019 KiB

Open AccessArticle

Effect of Porcine Akirin2 on Skeletal Myosin Heavy Chain Isoform Expression

by Xiaoling Chen¹, Yanliu Luo¹, Bo Zhou¹, Zhiqing Huang^1,*, Gang Jia¹, Guangmang Liu¹, Hua Zhao¹, Zhouping Yang² and Ruinan Zhang¹

¹ Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, Sichuan, China

² College of Science, Sichuan Agricultural University, Chengdu 611130, Sichuan, China

Int. J. Mol. Sci. 2015, 16(2), 3996-4006; https://doi.org/10.3390/ijms16023996 - 12 Feb 2015

Cited by 10 | Viewed by 5749

Abstract

Akirin2 plays an important role in skeletal myogenesis. In this study, we found that porcine Akirin2 (pAkirin2) mRNA level was significantly higher in fast extensor digitorum longus (EDL) and longissimus lumborum (LL) muscles than in slow soleus (SOL) muscle of pigs. [...] Read more.

Akirin2 plays an important role in skeletal myogenesis. In this study, we found that porcine Akirin2 (pAkirin2) mRNA level was significantly higher in fast extensor digitorum longus (EDL) and longissimus lumborum (LL) muscles than in slow soleus (SOL) muscle of pigs. Overexpression of pAkirin2 increased the number of myosin heavy chain (MHC)-positive cells, indicating that pAkirin2 promoted myoblast differentiation. We also found that overexpression of pAkirin2 increased the mRNA expressions of MHCI and MHCIIa and decreased the mRNA expression of MHCIIb. Myocyte enhancer factor 2 (MEF2) and nuclear factor of activated T cells (NFAT) are the major downstream effectors of calcineurin. Here we also observed that the mRNA expressions of MEF2C and NFATc1 were notably elevated by pAkirin2 overexpression. Together, our data indicate that the role of pAkirin2 in modulating MHCI and MHCIIa expressions may be achieved through calcineurin/NFATc1 signaling pathway. Full article

(This article belongs to the Section Biochemistry)

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21 pages, 2410 KiB

Open AccessArticle

Multiscale Experimental and Theoretical Investigations of Spin Crossover Fe^II Complexes: Examples of [Fe(phen)₂(NCS)₂] and [Fe(PM-BiA)₂(NCS)₂]

by Samir F. Matar^*, Philippe Guionneau^† and Guillaume Chastanet^†

¹ CNRS, Univ. Bordeaux, ICMCB, UPR 9048, F-33600 Pessac, France

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 4007-4027; https://doi.org/10.3390/ijms16024007 - 12 Feb 2015

Cited by 16 | Viewed by 8271

Abstract

For spin crossover (SCO) complexes, computation results are reported and confirmed with experiments at multiscale levels of the isolated molecule and extended solid on the one hand and theory on the other hand. The SCO phenomenon which characterizes organometallics based on divalent iron [...] Read more.

For spin crossover (SCO) complexes, computation results are reported and confirmed with experiments at multiscale levels of the isolated molecule and extended solid on the one hand and theory on the other hand. The SCO phenomenon which characterizes organometallics based on divalent iron in an octahedral FeN₆-like environment with high spin (HS) and low spin (LS) states involves the LS/HS switching at the cost of small energies provided by temperature, pressure or light, the latter connected with Light-Induced Excited Spin-State Trapping (LIESST) process. Characteristic infra red (IR) and Raman vibration frequencies are computed within density functional theory (DFT) framework. In [Fe(phen)₂(NCS)₂] a connection of selected frequencies is established with an ultra-fast light-induced LS → HS photoswitching mechanism. In the extended solid, density of state DOS and electron localization function (ELF) are established for both LS and HS forms, leading to characterizion of the compound as an insulator in both spin states with larger gaps for LS configuration, while keeping molecular features in the solid. In [Fe(PM-BiA)₂(NCS)₂], by combining DFT and classical molecular dynamics, the properties and the domains of existence of the different phases are obtained by expressing the potential energy surfaces in a short range potential for Fe–N interactions. Applying such Fe–N potentials inserted in a classical force field and carrying out molecular dynamics (MD) in so-called “semi-classical MD” calculations, lead to the relative energies of HS/LS configurations of the crystal and to the assessment of the experimental (P, T) phase diagram. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2015)

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15 pages, 2436 KiB

Open AccessArticle

Functional Properties of the Catalytic Domain of Mouse Acidic Mammalian Chitinase Expressed in Escherichia coli

by Akinori Kashimura^1,†, Masahiro Kimura^1,†, Kazuaki Okawa^1,†, Hirotaka Suzuki¹, Atsushi Ukita¹, Satoshi Wakita¹, Kana Okazaki¹, Misa Ohno¹, Peter O. Bauer², Masayoshi Sakaguchi¹, Yasusato Sugahara¹ and Fumitaka Oyama^1,*

¹ Department of Applied Chemistry, Kogakuin University, Hachioji, Tokyo 192-0015, Japan

² Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 4028-4042; https://doi.org/10.3390/ijms16024028 - 13 Feb 2015

Cited by 24 | Viewed by 6852

Abstract

Mouse acidic mammalian chitinase (AMCase) plays important physiological roles in defense and nutrition. AMCase is composed of an N-terminal catalytic domain (CatD) and a C-terminal chitin-binding domain (CBD). We expressed CatD of mouse AMCase as a recombinant fusion protein with Protein [...] Read more.

Mouse acidic mammalian chitinase (AMCase) plays important physiological roles in defense and nutrition. AMCase is composed of an N-terminal catalytic domain (CatD) and a C-terminal chitin-binding domain (CBD). We expressed CatD of mouse AMCase as a recombinant fusion protein with Protein A and V5-His in Escherichia coli (Protein A-CatD-V5-His), evaluated its functional properties and compared them to the full-length AMCase (Protein A-AMCase-V5-His). Under our experimental conditions, the chitinolytic activity of both proteins against 4-nitrophenyl N,N'-diacetyl-β-d-chitobioside was equivalent with regard to their specific enzymatic activities, optimal pH and temperature as well as to the pH and temperature stability. CatD bound to chitin beads and cleaved the N-acetylglucosamine hexamer, colloidal and crystalline chitin as well as the shrimp shell, and released primarily N,N'-diacetylchitobiose fragments at pH 2.0. These results indicate that the primary structure of CatD is sufficient to form a proper tertiary structure required for chitinolytic activity, recognize chitin substrates and degrade them in the absence of a CBD. Our recombinant proteins can be used for further studies evaluating pathophysiological roles of AMCase in different diseases. Full article

(This article belongs to the Section Biochemistry)

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25 pages, 764 KiB

Open AccessReview

Induced Pluripotent Stem Cells and Their Use in Cardiac and Neural Regenerative Medicine

by Stepanka Skalova^†, Tereza Svadlakova^†, Wasay Mohiuddin Shaikh Qureshi^†, Kapil Dev and Jaroslav Mokry^*

¹ Department of Histology and Embryology, Medical Faculty in Hradec Kralove, Charles University in Prague, Simkova 870, Hradec Kralove 50038, Czech Republic

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 4043-4067; https://doi.org/10.3390/ijms16024043 - 13 Feb 2015

Cited by 16 | Viewed by 10452

Abstract

Stem cells are unique pools of cells that are crucial for embryonic development and maintenance of adult tissue homeostasis. The landmark Nobel Prize winning research by Yamanaka and colleagues to induce pluripotency in somatic cells has reshaped the field of stem cell research. [...] Read more.

Stem cells are unique pools of cells that are crucial for embryonic development and maintenance of adult tissue homeostasis. The landmark Nobel Prize winning research by Yamanaka and colleagues to induce pluripotency in somatic cells has reshaped the field of stem cell research. The complications related to the usage of pluripotent embryonic stem cells (ESCs) in human medicine, particularly ESC isolation and histoincompatibility were bypassed with induced pluripotent stem cell (iPSC) technology. The human iPSCs can be used for studying embryogenesis, disease modeling, drug testing and regenerative medicine. iPSCs can be diverted to different cell lineages using small molecules and growth factors. In this review we have focused on iPSC differentiation towards cardiac and neuronal lineages. Moreover, we deal with the use of iPSCs in regenerative medicine and modeling diseases like myocardial infarction, Timothy syndrome, dilated cardiomyopathy, Parkinson’s, Alzheimer’s and Huntington’s disease. Despite the promising potential of iPSCs, genome contamination and low efficacy of cell reprogramming remain significant challenges. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Regeneration and Tissue Repair)

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15 pages, 1062 KiB

Open AccessReview

The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review

by Devin M. Cox^*,† and Merlin G. Butler^†

¹ Departments of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 4015, Kansas City, KS 66160, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 4068-4082; https://doi.org/10.3390/ijms16024068 - 13 Feb 2015

Cited by 165 | Viewed by 24552

Abstract

Patients with the 15q11.2 BP1–BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1–BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, [...] Read more.

Patients with the 15q11.2 BP1–BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1–BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%–1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Review of clinical features from about 200 individuals were grouped into five categories and included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores ≤75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%). Other clinical features noted but not considered as common were seizures/epilepsy (26%), autism spectrum disorder (27%), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms. Neuropsychiatric and behavior disturbances and mild dysmorphic features are associated with genomic imbalances of the 15q11.2 BP1–BP2 region, including microdeletions, but with an apparent incomplete penetrance and variable expressivity. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders)

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12 pages, 793 KiB

Open AccessReview

Autophagy as a Regulatory Component of Erythropoiesis

by Jieying Zhang^1,2, Kunlu Wu¹, Xiaojuan Xiao¹, Jiling Liao¹, Qikang Hu¹, Huiyong Chen¹, Jing Liu^1,* and Xiuli An^3,4

¹ State Key Laboratory of Medical Genetics & School of Life Sciences, Central South University, Changsha 410078, China

² Red Cell Physiology Laboratory, New York Blood Center, New York, NY 10065, USA

³ Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA

⁴ College of Life Science, Zhengzhou University, Zhengzhou 450001, China

Int. J. Mol. Sci. 2015, 16(2), 4083-4094; https://doi.org/10.3390/ijms16024083 - 13 Feb 2015

Cited by 56 | Viewed by 10709

Abstract

Autophagy is a process that leads to the degradation of unnecessary or dysfunctional cellular components and long-lived protein aggregates. Erythropoiesis is a branch of hematopoietic differentiation by which mature red blood cells (RBCs) are generated from multi-potential hematopoietic stem cells (HSCs). Autophagy plays [...] Read more.

Autophagy is a process that leads to the degradation of unnecessary or dysfunctional cellular components and long-lived protein aggregates. Erythropoiesis is a branch of hematopoietic differentiation by which mature red blood cells (RBCs) are generated from multi-potential hematopoietic stem cells (HSCs). Autophagy plays a critical role in the elimination of mitochondria, ribosomes and other organelles during erythroid terminal differentiation. Here, the modulators of autophagy that regulate erythroid differentiation were summarized, including autophagy-related (Atg) genes, the B-cell lymphoma 2 (Bcl-2) family member Bcl-2/adenovirus E1B 19 kDa interacting protein 3-like (Nix/Binp3L), transcription factors globin transcription factor 1 (GATA1) and forkhead box O3 (FoxO3), intermediary factor KRAB-associated protein1 (KAP1), and other modulators, such as focal adhesion kinase family-interacting protein of 200-kDa (FIP200), Ca²⁺ and 15-lipoxygenase. Understanding the modulators of autophagy in erythropoiesis will benefit the autophagy research field and facilitate the prevention and treatment of autophagy-related red blood cell disorders. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases)

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26 pages, 1768 KiB

Open AccessReview

The Actin Depolymerizing Factor (ADF)/Cofilin Signaling Pathway and DNA Damage Responses in Cancer

by Chun-Yuan Chang^1,†, Jyh-Der Leu^2,† and Yi-Jang Lee^1,3,*

¹ Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan

² Division of Radiation Oncology, Taipei City Hospital RenAi Branch, Taipei 106, Taiwan

³ Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei 112, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 4095-4120; https://doi.org/10.3390/ijms16024095 - 13 Feb 2015

Cited by 46 | Viewed by 18065

Abstract

The actin depolymerizing factor (ADF)/cofilin protein family is essential for actin dynamics, cell division, chemotaxis and tumor metastasis. Cofilin-1 (CFL-1) is a primary non-muscle isoform of the ADF/cofilin protein family accelerating the actin filamental turnover in vitro and in vivo. In response [...] Read more.

The actin depolymerizing factor (ADF)/cofilin protein family is essential for actin dynamics, cell division, chemotaxis and tumor metastasis. Cofilin-1 (CFL-1) is a primary non-muscle isoform of the ADF/cofilin protein family accelerating the actin filamental turnover in vitro and in vivo. In response to environmental stimulation, CFL-1 enters the nucleus to regulate the actin dynamics. Although the purpose of this cytoplasm-nucleus transition remains unclear, it is speculated that the interaction between CFL-1 and DNA may influence various biological responses, including DNA damage repair. In this review, we will discuss the possible involvement of CFL-1 in DNA damage responses (DDR) induced by ionizing radiation (IR), and the implications for cancer radiotherapy. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)

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15 pages, 704 KiB

Open AccessArticle

Genetic Polymorphisms in Estrogen-Related Genes and the Risk of Breast Cancer among Han Chinese Women

by Min-Ying Sun^1,†, Hong-Yan Du^2,†, An-Na Zhu², Hui-Ying Liang¹, Gorka Ruiz De Garibay³, Fen-Xia Li², Ming Li^2,* and Xue-Xi Yang^2,*

¹ Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China

² School of Biotechnology, Southern Medical University, Guangzhou 510515, China

³ Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, Barcelona 08908, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 4121-4135; https://doi.org/10.3390/ijms16024121 - 13 Feb 2015

Cited by 18 | Viewed by 6605

Abstract

Exposure to high levels of estrogen is considered an important risk factor for susceptibility to breast cancer. Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk, but no comprehensive study has been performed among Han Chinese women. [...] Read more.

Exposure to high levels of estrogen is considered an important risk factor for susceptibility to breast cancer. Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk, but no comprehensive study has been performed among Han Chinese women. In the present study, 32 single-nucleotide polymorphisms (SNPs) in estrogen-related genes were genotyped using the MassARRAY IPLEX platform in 1076 Han Chinese women. Genotypic and allelic frequencies were compared between case and control groups. Unconditional logistic regression was used to assess the effects of SNPs on breast cancer risk. Associations were also evaluated for breast cancer subtypes stratified by estrogen receptor (ER) and progesterone receptor (PR) status. Case-control analysis showed a significant relation between heterozygous genotypes of rs700519 and rs2069522 and breast cancer risk (OR = 0.723, 95% CI = 0.541–0.965, p = 0.028 and OR = 1.500, 95% CI = 1.078–2.087, p = 0.016, respectively). Subgroup comparisons revealed that rs2446405 and rs17268974 were related to ER status, and rs130021 was associated with PR status. Our findings suggest that rs700519 and rs2069522 are associated with susceptibility to breast cancer among the Han Chinese population and have a cumulative effect with three other identified SNPs. Further genetic and functional studies are needed to identify additional SNPs, and to elucidate the underlying molecular mechanisms. Full article

(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)

14 pages, 2083 KiB

Open AccessArticle

Isolation and Molecular Characterization of 1-Aminocyclopropane-1-carboxylic Acid Synthase Genes in Hevea brasiliensis

by Jia-Hong Zhu¹, Jing Xu², Wen-Jun Chang¹ and Zhi-Li Zhang^1,2,*

¹ Key Laboratory of Tropical Crop Biotechnology, Ministry of Agriculture, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China

² Hainan Academy of Agricultural Sciences, Haikou 571100, China

Int. J. Mol. Sci. 2015, 16(2), 4136-4149; https://doi.org/10.3390/ijms16024136 - 16 Feb 2015

Cited by 15 | Viewed by 6879

Abstract

Ethylene is an important factor that stimulates Hevea brasiliensis to produce natural rubber. 1-Aminocyclopropane-1-carboxylic acid synthase (ACS) is a rate-limiting enzyme in ethylene biosynthesis. However, knowledge of the ACS gene family of H. brasiliensis is limited. In this study, nine ACS-like genes [...] Read more.

Ethylene is an important factor that stimulates Hevea brasiliensis to produce natural rubber. 1-Aminocyclopropane-1-carboxylic acid synthase (ACS) is a rate-limiting enzyme in ethylene biosynthesis. However, knowledge of the ACS gene family of H. brasiliensis is limited. In this study, nine ACS-like genes were identified in H. brasiliensis. Sequence and phylogenetic analysis results confirmed that seven isozymes (HbACS1–7) of these nine ACS-like genes were similar to ACS isozymes with ACS activity in other plants. Expression analysis results showed that seven ACS genes were differentially expressed in roots, barks, flowers, and leaves of H. brasiliensis. However, no or low ACS gene expression was detected in the latex of H. brasiliensis. Moreover, seven genes were differentially up-regulated by ethylene treatment. These results provided relevant information to help determine the functions of the ACS gene in H. brasiliensis, particularly the functions in regulating ethylene stimulation of latex production. Full article

(This article belongs to the Section Biochemistry)

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11 pages, 820 KiB

Open AccessArticle

Major Peptides from Amaranth (Amaranthus cruentus) Protein Inhibit HMG-CoA Reductase Activity

by Rosana Aparecida Manólio Soares¹, Simone Mendonça^2,†, Luíla Ívini Andrade De Castro^1,†, Amanda Caroline Cardoso Corrêa Carlos Menezes^1,† and José Alfredo Gomes Arêas^1,*

¹ Faculty of Public Health, University of São Paulo, Av. Dr. Arnaldo, 715, São Paulo 01246-904, SP, Brazil

² EMBRAPA (Brazilian Corporation of Agricultural Research), PqEB, Brasília 70770-200, DF, Brazil

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 4150-4160; https://doi.org/10.3390/ijms16024150 - 16 Feb 2015

Cited by 113 | Viewed by 9138

Abstract

The objective of this study was to identify the major peptides generated by the in vitro hydrolysis of Amaranthus cruentus protein and to verify the effect of these peptides on the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), a key enzyme in cholesterol biosynthesis. [...] Read more.

The objective of this study was to identify the major peptides generated by the in vitro hydrolysis of Amaranthus cruentus protein and to verify the effect of these peptides on the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), a key enzyme in cholesterol biosynthesis. A protein isolate was prepared, and an enzymatic hydrolysis that simulated the in vivo digestion of the protein was performed. After hydrolysis, the peptide mixture was filtered through a 3 kDa membrane. The peptide profile of this mixture was determined by reversed phase high performance chromatography (RP-HPLC), and the peptide identification was performed by LC-ESI MS/MS. Three major peptides under 3 kDa were detected, corresponding to more than 90% of the peptides of similar size produced by enzymatic hydrolysis. The sequences identified were GGV, IVG or LVG and VGVI or VGVL. These peptides had not yet been described for amaranth protein nor are they present in known sequences of amaranth grain protein, except LVG, which can be found in amaranth α‑amylase. Their ability to inhibit the activity of HMG-CoA reductase was determined, and we found that the sequences GGV, IVG, and VGVL, significantly inhibited this enzyme, suggesting a possible hypocholesterolemic effect. Full article

(This article belongs to the Special Issue Bioactive Proteins and Peptides Derived from Food)

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19 pages, 1360 KiB

Open AccessReview

Biological Functions of Thyroid Hormone in Placenta

by Cheng-Yi Chen¹, Chie-Pein Chen^1,2 and Kwang-Huei Lin^3,*

¹ Department of Medical Research, Mackay Memorial Hospital, Taipei 251, Taiwan

² Division of High Risk Pregnancy, Mackay Memorial Hospital, Taipei 104, Taiwan

³ Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan 333, Taiwan

Int. J. Mol. Sci. 2015, 16(2), 4161-4179; https://doi.org/10.3390/ijms16024161 - 16 Feb 2015

Cited by 31 | Viewed by 8826

Abstract

The thyroid hormone, 3,3,5-triiodo-l-thyronine (T₃), modulates several physiological processes, including cellular growth, differentiation, metabolism, inflammation and proliferation, via interactions with thyroid hormone response elements (TREs) in the regulatory regions of target genes. Infection and inflammation are critical processes in placental development [...] Read more.

The thyroid hormone, 3,3,5-triiodo-l-thyronine (T₃), modulates several physiological processes, including cellular growth, differentiation, metabolism, inflammation and proliferation, via interactions with thyroid hormone response elements (TREs) in the regulatory regions of target genes. Infection and inflammation are critical processes in placental development and pregnancy-related diseases. In particular, infection is the leading cause of neonatal mortality and morbidity worldwide. However, to date, no successful approach has been developed for the effective diagnosis of infection in preterm infants. Pre-eclampsia (PE) is a serious disorder that adversely affects ~5% of human pregnancies. Recent studies identified a multiprotein complex, the inflammasome, including the Nod-like receptor (NLR) family of cytosolic pattern recognition receptors, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1, which plays a vital role in the placenta. The thyroid hormone modulates inflammation processes and is additionally implicated in placental development and disease. Therefore, elucidation of thyroid hormone receptor-regulated inflammation-related molecules, and their underlying mechanisms in placenta, should facilitate the identification of novel predictive and therapeutic targets for placental disorders. This review provides a detailed summary of current knowledge with respect to identification of useful biomarkers and their physiological significance in placenta. Full article

(This article belongs to the Section Biochemistry)

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10 pages, 708 KiB

Open AccessArticle

Genetic Variant in Interleukin-18 Is Associated with Idiopathic Recurrent Miscarriage in Chinese Han Population

by Jun Yue^1,†, Yu Tong^2,3,†, Jing Zhou⁴, Qingqing Liu^2,3 and Jiyun Yang^5,6,*

¹ Department of Gynecology & Obstetrics, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, No. 32, Section 2, the Western First Round Road, Chengdu 610072, China

² Laboratory of Early Developmental and Injuries, West China Institute of Woman and Children's Health, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nanlu, Chengdu 610072, China

³ Key Laboratory of Gynecologic & Obstetric and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu 610072, China

⁴ Department of Laboratory Medicines, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu 610072, China

⁵ Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, No. 32, Section 2, the Western First Round Road, Chengdu 610072, China

⁶ School of Medicine, University of Electronic Science and Technology of China, No. 32, Section 2, the Western First Round Road, Chengdu 610072, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 4180-4189; https://doi.org/10.3390/ijms16024180 - 16 Feb 2015

Cited by 16 | Viewed by 6418

Abstract

Levels of IL-18 were significantly lower in women with recurrent miscarriage (RM) than those without idiopathic RM. IL-18 promoter single nucleotide polymorphisms were previously identified to have an impact on IL18 gene transcription activity and influence the level of IL-18 protein production. The [...] Read more.

Levels of IL-18 were significantly lower in women with recurrent miscarriage (RM) than those without idiopathic RM. IL-18 promoter single nucleotide polymorphisms were previously identified to have an impact on IL18 gene transcription activity and influence the level of IL-18 protein production. The aim of this study was to evaluate whether IL-18 gene polymorphisms are risk factors for idiopathic RM in Chinese Han population. Study subjects comprised of 484 idiopathic RM patients and 468 controls. Three polymorphisms (rs360717, rs187238, rs1946518) in IL-18 gene and serum IL-18 concentrations were assessed. rs187238 variant exhibits significant association with RM in additive and recessive genetic model (additive model p = 1.05 × 10⁻⁴, dominant model p = 0.025, recessive model p = 2.43 × 10⁻⁵). In contrast, rs360717 and rs1946518 are not significantly associated with RM. Serum IL-18 levels are significantly lower in RM cases than in control (111.98 ± 93.13 versus 148.74 ± 130.51 pg/mL, p = 7.42 × 10⁻⁷). There are lower levels of serum IL-18 in rs187238 homozygous mutant (CC) than homozygous wild-type (GG) in this study population, including cases and control groups (98.31 ± 86.46 versus 131.87 ± 115.02 pg/mL, p = 0.015). These results suggest that reduced IL-18 levels and rs187238 variant may contribute to pathogenesis of idiopathic RM in Chinese Han population. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

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19 pages, 1310 KiB

Open AccessReview

The Role of BH3-Mimetic Drugs in the Treatment of Pediatric Hepatoblastoma

by Justus Lieber^*, Sorin Armeanu-Ebinger and Jörg Fuchs

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Hoppe-Seyler-Strasse 1, Tübingen D-72076, Germany

Int. J. Mol. Sci. 2015, 16(2), 4190-4208; https://doi.org/10.3390/ijms16024190 - 16 Feb 2015

Cited by 9 | Viewed by 8902

Abstract

Pediatric hepatoblastoma (HB) is commonly treated by neoadjuvant chemotherapy and surgical tumor resection according to international multicenter trial protocols. Complete tumor resection is essential and survival rates up to 95% have now been achieved in those tumors classified as standard-risk HB. Drug resistance [...] Read more.

Pediatric hepatoblastoma (HB) is commonly treated by neoadjuvant chemotherapy and surgical tumor resection according to international multicenter trial protocols. Complete tumor resection is essential and survival rates up to 95% have now been achieved in those tumors classified as standard-risk HB. Drug resistance and occurrence of metastases remain the major challenges in the treatment of HB, especially in high-risk tumors. These conditions urgently require the development of alternative therapeutic strategies. One of those alternatives is the modulation of apoptosis in HB cells. HBs regularly overexpress anti-apoptotic proteins of the Bcl-family in comparison to healthy liver tissue. This fact may contribute to the development of chemoresistance of HB cells. Synthetic small inhibitory molecules with BH3-mimetic effects, such as ABT-737 and obatoclax, enhance the susceptibility of tumor cells to different cytotoxic drugs and thereby affect initiator proteins of the apoptosis cascade via the intrinsic pathway. Besides additive effects on HB cell viability when used in combination with cytotoxic drugs, BH3-mimetics also play a role in preventing metastasation by reducing adhesion and inhibiting cell migration abilities. Presumably, including additive BH3-mimetic drugs into existing therapeutic regimens in HB patients might allow dose reduction of established cytotoxic drugs and thereby associated immanent side effects, while maintaining the antitumor activity. Furthermore, reduction of tumor growth and inhibition of tumor cell dissemination may facilitate complete surgical tumor resection, which is mandatory in this tumor type resulting in improved survival rates in high-risk HB. Currently, there are phase I and phase II clinical trials in several cancer entities using this potential target. This paper reviews the available literature regarding the use of BH3-mimetic drugs as single agents or in combination with chemotherapy in various malignancies and focuses on results in HB cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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17 pages, 2983 KiB

Open AccessArticle

Phosphoproteomic Analysis of the Highly-Metastatic Hepatocellular Carcinoma Cell Line, MHCC97-H

by Miaomiao Tian^1,†, Han Cheng^2,†, Zhiqiang Wang^1,3, Na Su¹, Zexian Liu², Changqing Sun⁴, Bei Zhen^1,*, Xuechuan Hong³, Yu Xue² and Ping Xu^1,3,*

¹ State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences, Beijing Institute of Radiation Medicine, Beijing 102206, China

² Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China

³ Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, and Wuhan University School of Pharmaceutical Sciences, Wuhan 430072, China

⁴ Tianjin Baodi Hospital, Tianjin 301800, China

^† These authors are equally contributed to this work.

Int. J. Mol. Sci. 2015, 16(2), 4209-4225; https://doi.org/10.3390/ijms16024209 - 16 Feb 2015

Cited by 26 | Viewed by 8850

Abstract

Invasion and metastasis of hepatocellular carcinoma (HCC) is a major cause for lethal liver cancer. Signaling pathways associated with cancer progression are frequently reconfigured by aberrant phosphorylation of key proteins. To capture the key phosphorylation events in HCC metastasis, we established a methodology [...] Read more.

Invasion and metastasis of hepatocellular carcinoma (HCC) is a major cause for lethal liver cancer. Signaling pathways associated with cancer progression are frequently reconfigured by aberrant phosphorylation of key proteins. To capture the key phosphorylation events in HCC metastasis, we established a methodology by an off-line high-pH HPLC separation strategy combined with multi-step IMAC and LC–MS/MS to study the phosphoproteome of a metastatic HCC cell line, MHCC97-H (high metastasis). In total, 6593 phosphopeptides with 6420 phosphorylation sites (p-sites) of 2930 phosphoproteins were identified. Statistical analysis of gene ontology (GO) categories for the identified phosphoproteins showed that several of the biological processes, such as transcriptional regulation, mRNA processing and RNA splicing, were over-represented. Further analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations demonstrated that phosphoproteins in multiple pathways, such as spliceosome, the insulin signaling pathway and the cell cycle, were significantly enriched. In particular, we compared our dataset with a previously published phosphoproteome in a normal liver sample, and the results revealed that a number of proteins in the spliceosome pathway, such as U2 small nuclear RNA Auxiliary Factor 2 (U2AF2), Eukaryotic Initiation Factor 4A-III (EIF4A3), Cell Division Cycle 5-Like (CDC5L) and Survival Motor Neuron Domain Containing 1 (SMNDC1), were exclusively identified as phosphoproteins only in the MHCC97-H cell line. These results indicated that the phosphorylation of spliceosome proteins may participate in the metastasis of HCC by regulating mRNA processing and RNA splicing. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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24 pages, 1532 KiB

Open AccessReview

Potential Role of Dipeptidyl Peptidase IV in the Pathophysiology of Heart Failure

by Thiago A. Salles¹, Leonardo Dos Santos², Valério G. Barauna² and Adriana C. C. Girardi^1,*

¹ Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-000, SP, Brazil

² Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria 29043-900, ES, Brazil

Int. J. Mol. Sci. 2015, 16(2), 4226-4249; https://doi.org/10.3390/ijms16024226 - 16 Feb 2015

Cited by 19 | Viewed by 9698

Abstract

Dipeptidyl peptidase IV (DPPIV) is a widely expressed multifunctional serine peptidase that exists as a membrane-anchored cell surface protein or in a soluble form in the plasma and other body fluids. Numerous substrates are cleaved at the penultimate amino acid by DPPIV, including [...] Read more.

Dipeptidyl peptidase IV (DPPIV) is a widely expressed multifunctional serine peptidase that exists as a membrane-anchored cell surface protein or in a soluble form in the plasma and other body fluids. Numerous substrates are cleaved at the penultimate amino acid by DPPIV, including glucagon-like peptide-1 (GLP-1), brain natriuretic peptide (BNP) and stromal cell-derived factor-1 (SDF-α), all of which play important roles in the cardiovascular system. In this regard, recent reports have documented that circulating DPPIV activity correlates with poorer cardiovascular outcomes in human and experimental heart failure (HF). Moreover, emerging evidence indicates that DPPIV inhibitors exert cardioprotective and renoprotective actions in a variety of experimental models of cardiac dysfunction. On the other hand, conflicting results have been found when translating these promising findings from preclinical animal models to clinical therapy. In this review, we discuss how DPPIV might be involved in the cardio-renal axis in HF. In addition, the potential role for DPPIV inhibitors in ameliorating heart disease is revised, focusing on the effects of the main DPPIV substrates on cardiac remodeling and renal handling of salt and water. Full article

(This article belongs to the Special Issue Pathogenesis of Cardiac Arrhythmias and Heart Failure)

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15 pages, 791 KiB

Open AccessArticle

Cultivation of Chlorella vulgaris and Arthrospira platensis with Recovered Phosphorus from Wastewater by Means of Zeolite Sorption

by Giorgos Markou^1,*

, Orily Depraetere², Dries Vandamme² and Koenraad Muylaert²

¹ Department of Natural Resources Management and Agricultural Engineering, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece

² Laboratory Aquatic Biology, KU Leuven Kulak, E. Sabbelaan 53, Kortrijk 8500, Belgium

Int. J. Mol. Sci. 2015, 16(2), 4250-4264; https://doi.org/10.3390/ijms16024250 - 16 Feb 2015

Cited by 30 | Viewed by 7348

Abstract

In this study, zeolite was employed for the separation and recovery of P from synthetic wastewater and its use as phosphorus (P) source for the cultivation of the green microalga Chlorella vulgaris and the cyanobacterium Arthrospira (Spirulina) platensis. At P-loaded zeolite concentration [...] Read more.

In this study, zeolite was employed for the separation and recovery of P from synthetic wastewater and its use as phosphorus (P) source for the cultivation of the green microalga Chlorella vulgaris and the cyanobacterium Arthrospira (Spirulina) platensis. At P-loaded zeolite concentration of 0.15–1 g/L, in which P was limited, the two species displayed quite different behavior regarding their growth and biomass composition. C. vulgaris preferred to increase the intracellular P and did not synthesize biomass, while A. platensis synthesized biomass keeping the intracellular P as low as possible. In addition under P limitation, C. vulgaris did display some little alteration of the biomass composition, while A. platensis did it significantly, accumulating carbohydrates around 70% from about 15%–20% (control). Both species could desorb P from zeolite biologically. A. platensis could recover over 65% and C. vulgaris 25% of the P bounded onto zeolite. When P-loaded zeolite concentration increased to 5 g/L, P was adequate to support growth for both species. Especially in the case of C. vulgaris, growth was stimulated from the presence of P-loaded zeolite and produced more biomass compared to the control. Full article

(This article belongs to the Special Issue Green Chemistry and the Biorefinery)

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16 pages, 2267 KiB

Open AccessArticle

β-Hydroxybutyric Sodium Salt Inhibition of Growth Hormone and Prolactin Secretion via the cAMP/PKA/CREB and AMPK Signaling Pathways in Dairy Cow Anterior Pituitary Cells

by Shou-Peng Fu^1,2,†, Wei Wang^1,†, Bing-Run Liu^1,†, Huan-Min Yang^2,†, Hong Ji^2,†, Zhan-Qing Yang¹, Bin Guo¹, Ju-Xiong Liu^1,* and Jian-Fa Wang^1,2,*

¹ College of Veterinary Medicine, Jilin University, Changchun 130062, China

² College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(2), 4265-4280; https://doi.org/10.3390/ijms16024265 - 16 Feb 2015

Cited by 15 | Viewed by 11146

Abstract

β-hydroxybutyric acid (BHBA) regulates the synthesis and secretion of growth hormone (GH) and prolactin (PRL), but its mechanism is unknown. In this study, we detected the effects of BHBA on the activities of G protein signaling pathways, AMPK-α activity, GH, and PRL [...] Read more.

β-hydroxybutyric acid (BHBA) regulates the synthesis and secretion of growth hormone (GH) and prolactin (PRL), but its mechanism is unknown. In this study, we detected the effects of BHBA on the activities of G protein signaling pathways, AMPK-α activity, GH, and PRL gene transcription, and GH and PRL secretion in dairy cow anterior pituitary cells (DCAPCs). The results showed that BHBA decreased intracellular cAMP levels and a subsequent reduction in protein kinase A (PKA) activity. Inhibition of PKA activity reduced cAMP response element-binding protein (CREB) phosphorylation, thereby inhibiting GH and PRL transcription and secretion. The effects of BHBA were attenuated by a specific G_αi inhibitor, pertussis toxin (PTX). In addition, intracellular BHBA uptake mediated by monocarboxylate transporter 1 (MCT1) could trigger AMPK signaling and result in the decrease in GH and PRL mRNA translation in DCAPCs cultured under low-glucose and non-glucose condition when compared with the high-glucose group. This study identifies a biochemical mechanism for the regulatory action of BHBA on GH and PRL gene transcription, translation, and secretion in DCAPCs, which may be one of the factors that regulate pituitary function during the transition period in dairy cows. Full article

(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)

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25 pages, 1621 KiB

Open AccessReview

Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in “Omics” Medicine

by Gianluigi Zaza^*

, Simona Granata^*

, Paola Tomei, Alessandra Dalla Gassa and Antonio Lupo

Renal Unit, Department of Medicine, University of Verona, Piazzale A. Stefani, 1, 37126 Verona, Italy

Int. J. Mol. Sci. 2015, 16(2), 4281-4305; https://doi.org/10.3390/ijms16024281 - 17 Feb 2015

Cited by 29 | Viewed by 11279

Abstract

Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over [...] Read more.

Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies. Full article

(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)

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21 pages, 5104 KiB

Open AccessArticle

Comprehensive Analysis Suggests Overlapping Expression of Rice ONAC Transcription Factors in Abiotic and Biotic Stress Responses

by Lijun Sun^1,2, Lei Huang¹, Yongbo Hong¹, Huijuan Zhang¹, Fengming Song¹ and Dayong Li^1,*

¹ National Key Laboratory for Rice Biology, Institute of Biotechnology, Zhejiang University, Hangzhou, Zhejiang 310029, China

² Institute of Analytical Chemistry for Life Science, School of Public Health, Nantong University, Nantong 226019, China

Int. J. Mol. Sci. 2015, 16(2), 4306-4326; https://doi.org/10.3390/ijms16024306 - 17 Feb 2015

Cited by 50 | Viewed by 8547

Abstract

NAC (NAM/ATAF/CUC) transcription factors comprise a large plant-specific gene family that contains more than 149 members in rice. Extensive studies have revealed that NAC transcription factors not only play important roles in plant growth and development, but also have functions in regulation of [...] Read more.

NAC (NAM/ATAF/CUC) transcription factors comprise a large plant-specific gene family that contains more than 149 members in rice. Extensive studies have revealed that NAC transcription factors not only play important roles in plant growth and development, but also have functions in regulation of responses to biotic and abiotic stresses. However, biological functions for most of the members in the NAC family remain unknown. In this study, microarray data analyses revealed that a total of 63 ONAC genes exhibited overlapping expression patterns in rice under various abiotic (salt, drought, and cold) and biotic (infection by fungal, bacterial, viral pathogens, and parasitic plants) stresses. Thirty-eight ONAC genes exhibited overlapping expression in response to any two abiotic stresses, among which 16 of 30 selected ONAC genes were upregulated in response to exogenous ABA. Sixty-five ONAC genes showed overlapping expression patterns in response to any two biotic stresses. Results from the present study suggested that members of the ONAC genes with overlapping expression pattern may have pleiotropic biological functions in regulation of defense response against different abiotic and biotic stresses, which provide clues for further functional analysis of the ONAC genes in stress tolerance and pathogen resistance. Full article

(This article belongs to the Special Issue Plant Molecular Biology)

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16 pages, 4735 KiB

Open AccessArticle

Introducing a Semi-Coated Model to Investigate Antibacterial Effects of Biocompatible Polymers on Titanium Surfaces

by Andreas Winkel^1,*, Wibke Dempwolf², Eva Gellermann¹, Magdalena Sluszniak², Sebastian Grade¹, Wieland Heuer¹, Michael Eisenburger¹, Henning Menzel²

and Meike Stiesch¹

¹ Clinic for Prosthetic Dentistry and Biomedical Materials Science, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany

² Institute for Technical Chemistry, Braunschweig University of Technology, Hans-Sommer-Str. 10, D-38104 Braunschweig, Germany

Int. J. Mol. Sci. 2015, 16(2), 4327-4342; https://doi.org/10.3390/ijms16024327 - 17 Feb 2015

Cited by 21 | Viewed by 8014

Abstract

Peri-implant infections from bacterial biofilms on artificial surfaces are a common threat to all medical implants. They are a handicap for the patient and can lead to implant failure or even life-threatening complications. New implant surfaces have to be developed to reduce biofilm [...] Read more.

Peri-implant infections from bacterial biofilms on artificial surfaces are a common threat to all medical implants. They are a handicap for the patient and can lead to implant failure or even life-threatening complications. New implant surfaces have to be developed to reduce biofilm formation and to improve the long-term prognosis of medical implants. The aim of this study was (1) to develop a new method to test the antibacterial efficacy of implant surfaces by direct surface contact and (2) to elucidate whether an innovative antimicrobial copolymer coating of 4-vinyl-N-hexylpyridinium bromide and dimethyl(2-methacryloyloxyethyl) phosphonate (VP:DMMEP 30:70) on titanium is able to reduce the attachment of bacteria prevalent in peri-implant infections. With a new in vitro model with semi-coated titanium discs, we were able to show a dramatic reduction in the adhesion of various pathogenic bacteria (Streptococcus sanguinis, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis), completely independently of effects caused by soluble materials. In contrast, soft tissue cells (human gingival or dermis fibroblasts) were less affected by the same coating, despite a moderate reduction in initial adhesion of gingival fibroblasts. These data confirm the hypothesis that VP:DMMEP 30:70 is a promising antibacterial copolymer that may be of use in several clinical applications. Full article

(This article belongs to the Special Issue Antimicrobial Polymers)

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Int. J. Mol. Sci., Volume 16, Issue 2 (February 2015) – 125 articles , Pages 2269-4361

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